Chinese Herbal Medicine on Cardiovascular Diseases and the Mechanisms of Action

Herbs and Helpers

aC/ 1Department of Preventive medicine, Basic Medical College, Zhejiang Chinese Medical University, Hangzhou, China

aC/ 2School of Biomedical Sciences, Institute of Vascular Medicine and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China

Cardiovascular cancers are the principal cause of death worldwide. The potentially serious adverse effects of therapeutic narcotics lead to growing awareness of the role of Chinese herbal medicine in the treatment of cardiovascular diseases. Chinese herbal medicine has been widely used in many countries especially in China from relic; however, the mechanisms by which herbal medicine acts in the prevention and treatment of cardiovascular diseases are far from clear. In its consideration of the, we briefly describe the characteristics of Chinese herbal medicine by comparing with western medicine. Then we summarize the formulae and herbs/ natural products applied in the clinic and animal examines being sorted according to the specific cardiovascular diseases. Most importantly, we elaborate the existing investigations into mechanisms by which herbal compounds act at the cellular levels, including vascular smooth muscle cells, endothelial cells, cardiomyocytes and immune cells. Future research should focus on well-designed clinic trial, in-depth mechanic examine, investigations on side effects of herbs and narcotic interactions. Studies on developing new agents with effectiveness and safety from traditional Chinese medicine is a promising style for prevention and treatment of patients with cardiovascular diseases.

Cardiovascular cancers, mainly including atherosclerosis, hypertension, cardiac hypertrophy, myocardial infarction and heart failure, were the main cause of death worldwide. The increasing number of patients around the world suffered by CVDs indicates the need for innovative strategies for guys more efficient prevention and treatment. Currently, western medicine, CHM and integrative medicine are the three major models of health care around the world. The western medicine has been considered as the mainstream medical treatment. For instance, antithrombotic narcotics combined with timely reperfusion therapy, coronary artery bypass grafting or precutaneous coronary intervention are widely applied to patients with CVDs. Although a widespread proof demonstrated these therapeutic regimes effective in reducing cardiovascular events, the potentially serious adverse effects are still key challenges. Thus it inspired the search for alternative and complementary therapies for better management of CVDs. CHM generally applies some natural plant products including dietary factors or herbal medicines. There is growing awareness of the role of herbs in the prevention of CVDs and the possibility of their use in therapy( Li et al ., 2015 ). With the more successful clinic be applied in CHM in CVDs prevention and treatment, the effects of CHM have depicted greater attention, even in developed countries including the United States and Australia. In its consideration of the, we focus on both the clinic practices and experimental studies to summarize the application of plant products and mechanistic investigations.

Search Strategy

To review all studies immediately describing the application of CHM in CVDs, we used the keywords “cardiovascular” and “herbs” with restriction the search to title and/ or abstract. The initial search produced 281 outcomes. We then afterwards selected the articles based on our aims. Since there are lots of formulae widely used in clinic in China, Guidelines for Diagnosis and Treatment of Common Internal Diseases in Chinese Medicine was referred too. A total of 123 articles and 1 Chinese Guideline was ultimately included in the review.

Comparison Between CHM and Western Medicine

Chinese herbal medicine is characterized by” Holistic regulation ,” in which the organism is considered as a whole. With the equilibrium of the human body as the guidelines, practitioners of CHM pay more attention to the diseased patients rather than the suffered diseases itself. Particular western medicine always has a strong impact on a specific disease with focusing on a specific physiological target and dismissing the specific characteristics of each patient.

” Syndrome Differentiation based therapy” is another feature of traditional Chinese medicine, which entails diagnosis and therapy based on an overall analysis of the illness and practitioners timely modify formulae in accordance with the different syndromes and clinical manifestations. Thus, it is an individualized therapy for different patients even with the same cancer. Particular western medicine usually runs against a specific pathological process of cancers rather than a patient.

Many CHM and foods originate from the same source and the feature of” Homology of medicine and food” reflects that CHM has few adverse effects. Traditionally, some foods are preferred to drugs for health care, and certain kinds of herbs are regarded as foods. Hawthorn fruit and garlic are such examples. However, due to the strong pertinence, western medicine will unavoidably cause side effects. Although the efficacy of CHM is not as strong as chemicals on a pathological process of CVDs, the feature of individualized intervention with minimum adverse effects stimulates CHM would be a good option and will continue to construct great contributions to the health of CVDs patients.

Application of CHM in CVDs

Many experimental examines indicate that a great many herbs have potential benefits for CVDs. Herbal plant-based formulations or narcotics are pivotal to traditional practices and be applied in plant products as CHM therapy has been widely used in patients with hypertension, atherosclerosis, congestive heart failure, angina pectoris and other cardiovascular risk factors.

Application of Plant Products in Hypertension

Hypertension is a worldwide health problem with high morbidity and an important player in the onset of cancers such as atherosclerosis, stoke, peripheral artery cancer, heart failure and coronary artery cancer. Hypertension is defined as having a systolic BP of aY= 140 mmHg and a diastolic BP of aY= 90 mmHg. Every 20/10( systolic BP/ diastolic BP) mmHg increase indicates a higher risk stage of hypertension, stage 1( 140 -1 59/90 -9 9 mmHg) and stage 2( aY= 160/100 mmHg) with the latter stage necessitating immediate medical attention.

Notably, there are some formulae, many well known herbal products and their extracts or secondary metabolites of the herbs and spices exhibit antihypertensive consequences. Interestingly, in a population-based database enrolling 984 CHM users and 2434 non- CHM users with hypertension among type 2 diabetes patients, the CHM users were characterized with somewhat longer duration time from diabetes to hypertension, suggesting that CHM may restrain hypertension pathogenesis among type 2 diabetes patients( Lin et al ., 2015 ). Here, we present the most commonly used formulae and a comprehensive alphabetical list of plant products with proof suggesting beneficial in hypertension therapy.

Formulae

Yiqi Huaju Formula and Bushen Qinggan Formula are regularly is used in clinical practice for treating hypertension. Yiqi Huaju Formula consists of Gastrodia elata, Uncaria, Eucommia bark, radix Scutellariae, and bitter butyl tea. In a study with 43 hypertensive patients coupled with metabolic disorder, 12 weeks of additional employ of Yiqi Huaju Formula( along with anti-hypertensive narcotics) significantly decreased systolic BP and 24 -h BP variability in comparison with the control group( anti-hypertensive narcotics plus placebo ), indicating that Yiqi Huaju treatment may be better than antihypertensive narcotics alone( Chen et al ., 2013 ). Bushen Qinggan Formula consists of Astragali Mongholici, Rhizoma Coptidis, Pollen Typhae, Rhizoma Alismatis, and Artemisiae Capillaries. A favorable effect of Bushen Qinggan Formula was observed on control of BP variability level after 8 weeks of therapy in a randomized controlled pilot clinical trial( 150 patients with hypertension ). This was accompanied with reduced endothelin and elevated nitric oxide( NO )/ endothelin in circulation, indicating improved endothelial function( Wu et al ., 2014 ). In addition, according to the Guidelines for Diagnosis and Treatment of Common Internal Diseases in Chinese Medicine, there are some frequently used formulae for hypertension in clinic which are based on syndrome differentiation( China Association of Chinese Medicine, 2008 ). The formulae are listed in Table 1.

Natural Plant Products

Allium sativum L( Amaryllidaceae)

Allium sativum L is also called garlic. It receives emerging interest from pharmacologists and health practitioners with its multi therapeutic consequences, including hypotensive capacity, anti-inflammatory, antioxidant, antibacterial and hypocholesteremic properties. Among the garlic’s organo-sulfur constituents, allicin is the most responsible one. Fresh garlic immediately releases allicin while chewing, whereas dried garlic preparations lack allicin but contain both allinin and allinase which could convert allinin to allicin. Evidence from many investigations and meta-analysis of randomized, controlled trials concluded that garlic supplements induce significant reduction in mean arterial pressure, drop in either systolic BP or diastolic BP with different extent. Interestingly, some studies indicate that aged garlic extract makes consistent lowering of BP compared to other forms of garlic( Blesken, 1992 ). However, more experimentations are needed to confirm garlic’s impact on hypertension since some studies come with no conclusive result( Shao et al ., 2016 ). Despite having these multifarious consequences, garlic also makes a few minor side effects, including abdominal swelling, heartburn, flatulence, and acid reflux et al.

Andrographis paniculata( Acanthaceae)

Andrographis paniculata is a plant that is commonly known as the King of Bitter. Several hypotensive labdane-type diterpenoid compounds, andrographolide, 14 -deoxy- 11,12 -didehydroandrographolide and 14 -deoxyandrographolide have been identified in Andrographis paniculata extracts. Animal examines show that therapy with its extracts decrease angiotensin converting enzyme and ROS activities in SHRs leading to decrease in BP ( Zhang and Tan, 1996 ). Ex vivo examines demonstrate that the extracts reduce vascular resistance reflected by decreased coronary perfusion pressure in rat isolated hearts( Awang et al ., 2012 ). However , no clinic trials have yet been conducted using the King of bitter.

Apium graveolens L( Apiaceae)

Apium graveolens L is also known as celery. The hypotensive effect of celery has been reported in in vivo animal examines. The extracts of celery reduce BP in deoxycorticosterone acetate-induced hypertensive rats or animal model of SHR( Moghadam et al ., 2013 ). Importantly, extracts and constituents of celery have been reported to lower arterial pressure in humen, maybe by lowering high levels of circulating catecholamines and lessening vascular resistance( Houston, 2005 ).

Bidens pilosa L( Compositae)

Bidens pilosa L is also called Beggar’s Tick. It is native to America and belongs to the family Compositae. Extracts of its leaves were able to prevent and attenuate high BP in different hypertensive rat models, both SHR and fructose-fed hypertensive rats( Steiner et al ., 1996 ). In fructose-fed rats, 75 and 150 mg/ kg of methanolic leaf extract of B. pilosa, demonstrated both therapeutic and preventative impact on systolic BP ( Steiner et al ., 1996 ). However, clinical trials are required to determine the potential effect of this plant on hypertension.

Camellia sinensis( Theaceae)

Camellia sinensis, also known as tea, is most frequently eaten and merely second to water. Its cardiovascular protective impact is well known worldwide. Catechins, the major flavonoids in tea, include( -) – epicatechin,( -) -epicatechin-3-gallate,( -) – epigallocatechin, and( -) -epigallocatechin-3-gallate.( -) -epigallocatechin-3-gallate constitutes the primary component of tea’s total catechins. Although some trials come to conclusion of no change in BP subsequent to drinking tea, lots of studies suggest that tea consumption reduces both systolic BP and diastolic BP by a1/ 42 mmHg each. Interestingly, the green tea provokes a more powerful hypotensive impact compared to black tea.

Coptis chinensis( Ranunculaceae)

It’s commonly known as goldthread and widely used in Chinese folk medicine. The goldthread and its major component berberine, have the ability to lower BP . Indeed, a recent meta-analysis of twenty-seven randomized controlled trials involving 2569 patients reported that berberine can cause a significant hypotensive impact( Lan et al ., 2015 ). In addition, this meta-analysis concluded that combined with an oral hypotensor, berberine can significantly reduce BP more than the hypotensor alone can do. The magnitude of the decrease was at an average of 4.91 and 2 mmHg for systolic BP and diastolic BP, respectively( Lan et al ., 2015 ).

Crataegus spp.( Rosaceae)

It is also known as Hawthorn or Shanzha. The plants are shrubs that belong to a genus comprising virtually 300 species and have been used in traditional medicine for therapy of CVDs since the seventeenth century. Hawthorn is used to dissipate food accumulation, to improve blood circulation, and to scatter blood stasis. The antihypertensive actions should be credited to the plant’s multiple components: flavonoids( hyperoside, quercetin, rutin, and vitexin) and oligomeric proanthocyanidins( OPCs, epicatechin, procyanidin, and procyanidin B-2 ). Modest decreases in BP have been observed in a few human-based examines with a demographic of hypertensive patients( Walker et al ., 2002; Tassell et al ., 2010 ). In a randomized, double-blind, placebo-controlled examine where mildly hypertensive subjects were treated with 500 mg of hawthorn extract for 10 weeks, a promising tendency for a reduction in diastolic BP was reported( Walker et al ., 2002 ). In another clinic examine, administration of hydro-alcoholic extracts of hawthorn flowers to hypertensive patients( age range 40 -6 0 years) for 3 months induced a decrease in both systolic BP and diastolic BP by around 13 and 8 mmHg, respectively( Asgary et al ., 2004 ).

Crocus sativus L( Iridaceae)

Crocus sativus L, also known as Saffron, a plant indigenous to Southwest Asia, Spain, Greece, and Morocco, is a stemless herb. Saffron’s major component include crocin, picrocrocin, safranal, and crocetin. Several reports support the use of saffron for anti-hypertensive benefits. A clinical examine reports that 400 mg of Saffron tablets administered for 7 days are able to significantly reduce the systolic BP and mean arterial pressure in healthy humen by 11 and 5 mmHg, respectively( Modaghegh et al ., 2008 ). Six weeks old stroke-prone SHRs are given crocetin for 3 weeks and this therapy significantly moderates the increasing number of systolic BP fail to comply with age( Higashino et al ., 2014 ). Saffron also demonstrates vasorelaxant activities in different animal models, including male Sprague-Dawley rats( Fatehi et al ., 2003 ), stroke-prone SHRs( Higashino et al ., 2014 ), deoxycorticosterone acetate-salt induced hypertensive male Wistar rats( Imenshahidi et al ., 2010) but not normotensive rats( Imenshahidi et al ., 2015 ).

Hibiscus sabdariffa L( Malvaceae)

Also known as Roselle, Hibiscus sabdariffa is widely used for hypertension, fever, and other cancers in folk medicine. Different parts of this plant( buds, calyx, flowers, leaves, and petals- fresh or dried) are used for health purposes and as refreshing beverages, food items( jams, preserves ), or lotions. Hibiscus’s effects of hypotension have been extensively investigated in both animal and human examines( McKay et al ., 2010; Ojeda et al ., 2010; Inuwa et al ., 2012 ). The blood lowering consequences were notable subsequent to treatment with dried extract of Roselle calyx for 4 weeks in patients with stage 1 or 2 hypertension( Herrera-Arellano et al ., 2007 ). In addition, eating Roselle’s tea( 240 ml- three times a day for 6 weeks) considerably reduce systolic BP, diastolic BP, and mean arterial pressure by 7.2, 3.1, and 4.5 mmHg, respectively in mild and pre-hypertensive patients( 65 subjects, age range 30 -7 0 years old)( McKay et al ., 2010 ), supporting Hibiscus’ therapeutic role in ameliorating hypertension.

Hippophae rhamnoides L( Elaegnaceae)

Hippophae rhamnoides L is also called Saji or Sea buckthorn and its dry fruits are used in China as an herbal medicine. Analysis showed that the powder made of dry hippophae fruits contains the vitamins C, B1, B2 and E, provitamin A, rutin, serotonin, cytosterol, selenium and zinc. The stroke-prone SHR were fed ad libitum with blocks of rat chow supplemented with Hippophae powder and the effect of lowering BP was analyse. The mean arterial BP and heart rate were significantly decreased by the Hippophae treatment( Koyama et al ., 2009 ), which is in accord with previous examines showing that Hippophae extracts decreased intracellular Ca2+ in cultured VSMCs( Zhu et al ., 2005 ).

Nigella sativa L( Ranunculaceae)

Nigella sativa L, also known as Black Cumin or Habbatul barakah( seed of blessing ), has been used in the kitchens of Europe, the Middle East, Africa, and Asia for centuries. Thymoquinone, one of the most abundant and bioactive components, has been identified as the major component in its healing consequences. Similar to other herbs, N. sativa and its constituents have been shown to reduce BP in humans and different animal models of hypertension. N. sativa’s seed extract administrated orally( either 100 or 200 mg, two times per 24 h for 8 weeks) to mild hypertensive male patients recorded a dose-dependent fall in both systolic BP and diastolic BP ( Ried, 2016 ). Again, in a randomized, placebo-controlled, double-blind examine with 70 healthy subjects, N. sativa petroleum caused a significant decrease of 10. 6 mmHg in systolic BP and 9.6 mmHg in diastolic BP ( Fallah Huseini et al ., 2013 ).

Panax ginseng C.A. Mey( Araliaceae)

Panax ginseng, also called Panax or Renshen, has been used in folk medicine for several centuries. Ginseng is prepared and administered in various forms, either as a solid: tablets, capsules, dried roots; or as a liquid: petroleum, extracts or tea. There are four most common species of Ginseng, including P. ginseng( Asian or Korean Ginseng ), P. quinquefolius( American Ginseng ), P. japonicas( Japanese Ginseng) and P. notoginseng( Chinese Ginseng) are the four most common species of ginseng. Heterogeneous triterpenoid saponins and steroid glycosides or ginsenosides( or panaxosides) are the active principle components of ginseng. Several clinical trials have been conducted to assess the efficacy of ginseng in BP regulation. Both Asian/ Korean Ginseng extract and American Ginseng caused a significant decrease in systolic BP and diastolic BP in hypertensive patients( Mucalo et al ., 2013; Rhee et al ., 2014 ). The mode of action may be related with antagonizing a calcium ion channel in vascular tissues, which may result in lowering BP . However, conflicting the reporting of elevated BP also exist( Jang et al ., 2011; Kim, 2012 ). For instance, examines have shown that low dosages of ginseng create BP, while higher concentrations are hypotensive( Jang et al ., 2011 ), which need more experimentations to elucidate the differentiation.

Pueraria lobata( Willd) ohwi( Leguminosae)

It is also known as Kudzu root or Gegen. Kudzu root has traditionally been used in Chinese medicine for treating CVDs and Type II diabetes. It is a rich source of polyphenolic compounds, including isoflavones, isoflavonoid glycosides, coumarins, puerarols, but-2-enolides and their derivatives. Puerarols attract more attention to investigate the direct effect on BP . According to Wong’s review, the anti-hypertensive effect of puerarin was shown as early as 1980 s provide evidence of reduced BP, heart rate and plasma rennin activity in SHRs and this impact may be exerted through blocking the effect of I2-adrenergic receptors( Wong et al ., 2011 ). Verapamil is a positive control hindering Angiotensin II type I receptor and angiotensin-converting enzyme 2 in SHRs. Similar to it, puerarin therapy significantly repressed the mRNA high levels of Angiotensin II type I receptor and angiotensin-converting enzyme 2 in cardiac tissues( Ye et al ., 2008 ). Further interdisciplinary collaboration to bridge the gap between traditional medicine and modern biomedical medicine is needed for the development of Kudzu root as an effective medicine for the management of hypertension and other CVDs.

Salviae miltiorrhizae( Lamiaceae)

It is also known as Danshen, or red/ Chinese sage. Danshen is one of the oldest and most frequently eaten Chinese traditional herbs and is commonly used for the therapy of CVDs. Sal A, Sal B, Danshensu, and tanshinones are its most effective ingredients. A combining therapy of Danshen and Gegen was prove to lower BP in SHRs and to induce relaxation of several kinds of arteries including porcine coronary arteries, rat aorta, and basilar arteries( Al Disi et al ., 2015 ). Apart from its vasodilatory capacity, Danshen expresses additional anti-hypertensive parameters such as antioxidative, anti-proliferative, and anti-inflammatory activities which will be discussed in more details in Section” Mechanisms of Plant Products in the Attenuation of CVDs .”

Scutellaria baicalensis Georgi( Lamiaceae)

The dried roots of S. baicalensis, also known as Huangqin in China, have been widely employed in traditional CHM as popular antibacterial and antiviral agents. Baicalein and its glycoside, baicalin, are the major ingredients responsible for its beneficial effects. Its BP lowering impact in puppy and rat was reported as early as 1980′ s( Huang et al ., 2005 ). However, the baicalein exerts a complex impact on the agonist contracted rat mesenteric arteries. Within a relative low concentration range( 0.3 -1 0 I1/ 4M ), baicalein potentiates vasoconstricting responses to phenylephrine, U46619, or to elevated extracellular potassium in endothelium-intact artery rings( Chen et al ., 1999; Tsang et al ., 2000 ), whilst it makes relaxations at concentrations greater than 10 I1/ 4M( Chen et al ., 1999 ). Since the increased vessel contraction is absent upon removal of the endothelium while the relaxant effect of baicalein remains( Chen et al ., 1999 ), endothelium-derived vasoactive factors may be involved in the bidirectional impact on vascular function. To be specific, baicalein and baicalin increase the evoked contractile replies likely through inhibition of NO production and/ or release in the endothelium( Huang et al ., 2000, 2002; Tsang et al ., 2000 ). The mechanisms by which baicalein lowers BP will be discussed in Section” Regulating Calcium Levels in PKA/ PKG/ PKC-Dependent Way .”

Application of Plant Products in Atherosclerosis and Dyslipidemia

Atherosclerosis, one of the primary causes of CVDs, is a vascular cancer that occurs at susceptible sites in major arteries. It is an inflammatory process and ultimately causes stenosis or thrombosis with potentially lethal distal ischemia. The main elements involved in the complex pathogenesis of atherosclerosis include hyperlipidemia, endothelial injury, LDL subendothelial retention and oxidation, monocyte migration and activating, VSMC migration and proliferation, foam cell formation, apoptosis and efferocytosis and unresolved inflammation. Among them, dyslipidemia is the primary independent risk factors, which is characterized by elevated level of total cholesterol( TC ), triglyceride( TG ), LDL-C and by lowered level of high-density lipoprotein cholesterol( HDL-C) in serum.

The description of the clinical manifestations and therapy of atherosclerosis can be found in the classic traditional Chinese medicine book Inner Canon of yellow Emperor, as early as 500 BC. Atherosclerosis, dyslipidemia and its resulting heart disease have been treated with numerous herbal remedies for centuries. Then, we present a comprehensive alphabetical list of plant products which are most commonly used to attenuate atherosclerosis and lower hyperlipidemia.

Allium fistulosum L( Amaryllidaceae)

Allium fistulosum L is widely cultivated in Southern China . Treatment with Fistular onion stalk, the derivant from A. fistulosum ., induces a significant reduction in the average lesion region of atherosclerosis and preservation of the vascular wall and immune cell infiltration. The extract also reduces high levels of the inflammatory cytokines IL-1I 2, IL-6, MCP1 and TNFI +- and downregulated the local activity of the rennin-angiotensin-aldosterone system in the aortic tissue. In addition, extract therapy inhibits several local inflammatory signaling pathways by preventing its activating, including phosphorylation of the NFIoB, Janus kinase/ signal transducers and activators of transcription and mitogen-activated protein kinase pathways( He B. et al ., 2014 ). These data indicate that fistular onion stem extract may be useful for the attenuation of atherosclerosis, and the mechanism includes the regulation of the local inflammatory responses.

Allium sativum L( Amaryllidaceae)

In addition to the anti-hypertensive impact, i still have broad spread belief among general public that Allium sativum L( garlic) has beneficial effects on dyslipidemia in patients. Seventy type 2 diabetes patients with newly diagnosed dyslipidemia split into two groups and were given tablet garlic 300 mg( containing 1.3% allicin) twice daily and identical placebo tablets respectively. 12 -week of garlic therapy induces a significant reduction in TC and LDL-C, a significant increase in HDL-C( Ashraf et al ., 2005 ). In a double-blind, crossover examine of moderately hypercholesterolemic men, therapy with 7.2 g aged garlic extract induced a maximal decrease of 6.1% in serum TC levels and 4.6% in LDL cholesterol levels( Steiner et al ., 1996 ). These consequences were Although one recent meta-analysis concluded that garlic reductions TC to a modest extent, an effect driven mostly by the modest decreases in TG, with no appreciable impact on LDL or HDL cholesterol( Reinhart et al ., 2009 ), many studies indicate garlic to be effective in improving lipid metabolism( Ried, 2016 ). Since some meta-analysis has been based on trials with inadequate examine designs, methodological inadequacies, the effect of garlic on atherosclerosis and dyslipidemia awaits further investigation.

Astragalus propinquus( Fabaceae)

The dried root of Astragalus propinquus, Radix Astragali, is also known as Huangqi. Polysaccharides, flavonoids, and sponins are the main active components of membranous milkvetch root. Studies have shown that Huangqi extract significantly decreased the area of atherosclerosis plaques( 17.24% A +- 4.22% vs. 49.87% A +- 9.37%, P <0.01) and level of serum oxldl (5.2 a+- 6.1 i1/4g/ml vs. 15.8 a+- 5.4 i1/4g/ml, p <0.01) in apoe-/- mice (you et al., 2012). effects of its extract and components on lipid profile are also summarized in a review, in which the serum of tg, tc, and ldl-c levels were reduced by both astragalus mongholicus extracts treatment at 0.4 and 0.8% for 5 weeks and polysaccharides from astragalus administered at an oral dosage of 40 mg, 100 mg/kg/day in hyperlipidemia rats for 40 days (guo et al., 2014). accordingly, the hdl-c levels were increased by these treatments (guo et al., 2014).

Coptis chinensis Franch. (Ranunculaceae)

Rhizoma Coptidis, also known as Huanglian, is derived from the dried root and rhizome of Coptis chinensis Franch., Coptis deltoidea C. Y. Cheng et Hsiao, and Coptis teeta Wall. Its main components include lignans and alkaloid, in which berberine is the active component for lipid lowering. Because of berberine’s active effect for lipid lowering, most of the studies focus on this component. Studies have shown that berberine administration significantly decreased the serum TG, TC, LDL-C, when taken orally or injected intraperitoneally (Zhou et al., 2008; Chang et al., 2012). In addition, Caucasian obese human subjects were orally given 500 mg berberine, three times a day for 12 weeks. The blood lipid was significantly reduced and TG, TC were decreased by 23 and 12.2%, respectively (Hu et al., 2012). In a meta-analysis, berberine induced a significant reduction in these biomarkers in 874 participants in11 randomized controlled trials (Ma et al., 2013).

Crataegus spp. (Rosaceae)

Known as hawthorn, its hypolipidemia effect has been investigated widely in animal studies. In high-fat diets fed mice, the oral administration of the whole extract at a dosage of 250 mg/kg/day for 7 days induced blood lipid decrement (Niu et al., 2011). Then, the specific effects of aqueous and ethanol extracts of hawthorn on lipid profiles were compared. In a high-fat emulsion fed mice, both ethanol and aqueous extracts possessed hypolipidemia activities and the ethanol extract exhibited more favorable effects than the aqueous extract (Shao et al., 2016). This lipid lowering effect of hawthorn mostly contributes to inhibition of the progression of atherosclerosis which was evidenced by the significantly inhibited pathological changes and reduced intima-media thickness in the arteries (Zhang et al., 2013). In-depth exploration demonstrated that the lipid-lowering action may be due to the anti-inflammation activities, the upregulation of PPARI+- to facilitate I2-oxidation-related enzymes in liver leading to lipid degradation, enhanced expression of hepatic LDL receptors resulting in a greater influx of plasma cholesterol into the liver, and the suppressed cholesterol biosynthesis and increased degradation of cholesterol to bile acids (Niu et al., 2011; Walden and Tomlinson, 2011; Zhang et al., 2013; Shao et al., 2016). The hypolipidemic effects of hawthorn in clinic remain further study.

Epimedium brevicornum Maxim (Berberidaceae)

Epimedium brevicornum Maxim, an important traditional CHM, has been used widely for 1000s of years in China, Korea, and Japan. Icariin, a flavonoid isolated from Epimedium brevicornum Maxim, is considered as the main pharmacological active constituent. In the high cholesterol diet-induced atherosclerosis rats, the levels of blood lipids including TC, TG, LDL-C, and malonaldehyde were significantly increased, while HDL-C and SOD were significantly decreased. Icariin succeeded in improving these biochemical parameters toward the normal values (Hu et al., 2016).

Fallopia multiflora Thunb. (Polygonaceae)

Its dried root tuber is Radix Polygoni Multiflori, also known as Heshouwu. Raw and prepared pharmaceutical forms are frequently used. Guo et al. (2014) reviewed the hypolipidemic effect of Heshouwu from some Chinese literature which demonstrated that the total extract of the Radix Polygoni Multiflori significantly reduced the serum levels of TC, TG and LDL-C in hyperlipidemic rats when administered at an oral dosage of 12 mg and 24 mg/ kg/ day for 4 weeks. Similarly, these lipid profiles in the hyperlipidemic rats were lowered by the therapy of the ethlacetate extracting fraction and stilbene glycoside from the tube of Radix Polygonum Multiflorum too( Guo et al ., 2014 ).

Fermentum Rubrum( Aspergillaceae)

Fermentum Rubrum, popularly known asred yeast rice, is the fermented product of Monascus purpureus on rice. It is composed of 13 kinds of natural statins, unsaturated fatty acids, ergosterol, amino acids, flavonoids, alkaloid, trace element, and so forth. Some clinic examines have demonstrated the lipid lowering effects of the red yeast rice. A twice daily dosage of red yeast rice at 600 mg for 8 weeks was found to reduce LDL-C by 27.7%, TG by 21.5%, and TC by 15.8%( Lin et al ., 2005 ). Similar consequences were observed in 72 patients with idiopathic persistent nephritic disorder with secondary dyslipidemia( Gheith et al ., 2008, 2009 ). Xuezhikang capsule is the extract of red yeast rice. Intellectuals in China made a systematic review on the clinical randomized controlled trials for hyperlipidemia therapy with Xuezhikang, which included a total of 6520 participants in 22 randomized trials. It was concluded that Xuezhikang remarkably lowered TC, TG, and LDL-C compared with the inositol nicotinate( Fallah Huseini et al ., 2013 ).

Olea europaea L.( Oleaceae)

The beneficial effects of Olea europaeal L ., especially olive foliage extract are known since relic, with numerous records corroborating its therapeutic employ. According to the European Pharmacopeia, the most abundant substances in standardized dry foliage extracts are oleuropein, hydroxytyrosol, caffeic acid, tyrosol, apigenin, and verbascoside, with oleuropein being the major component of olive foliage extract. Olive leaf extract therapy reduces the atherosclerostic lesions size and the thickness of intima in atherosclerotic rabbits, accompanied with reduced high levels of atherosclerotic markers, including serum TG, TC, LDL, HDL, and malonaldehyde with a parallel downregulation of MCP1, vascular cell adhesion molecule-1, NFkB and TNFI +-( Wang et al ., 2008 ). Consistent with it, another animal examine showed that a 1-month intake of hydroxytyrosol by rabbits eating an atherogenic diet outcomes in a reduced size of atherosclerotic lesions compared to control animals( Gonzalez-Santiago et al ., 2006 ). However, research results originating from in vivo models are divergent. The intake of hydroxytyrosol in an in vivo apo-E knockout mouse model showed that this compound, when administered for 10 weeks, have contributed to atherosclerotic lesions associated with the activation of monocytes and modification of the blood lipid profile( Acin et al ., 2006 ). These examines indicate that under certain conditions the phenol could be rather harmful than cytoprotective.

Panax ginseng C.A. Mey( Araliaceae)

The resources and components have been discussed in Section” Application of Plant Products in Hypertension .” A serious of studies has demonstrated the hypolipidemic effects of its components. For instance, high levels of plasma TC, TG, and LDL-c in C57/ BL-ApoE gene knockout hyperlipidemia rats were reduced by intragastric administration of ginseng saponins at an oral dosage of 2 mg/ kg/ day for 90 days. Ginseng saponin is divided into Rb1, Rb2, RC, Rd, Re, and Rl. Ginseng saponin Rb administered at an oral dosage of 50-200 mg/ kg/ day in hyperlipidemia rat for 12 days significantly reduce the TG, TC, and LDL-c levels in serum and liver( Yue et al ., 2012 ). Ginseng radix can be metabolized into compound k in small intestinal. In vitro, the metabolites significantly activate the AMP-activated protein kinase( AMPK) to affect the lipid metabolism in insulin-resistant HepG2 human hepatoma cells( Kim et al ., 2009 ).

Pueraria lobata( Willd) ohwi( Leguminosae)

Also known as Kudzu Root, its effects on hyperlipidemia are investigated in a series of studies. Puerarin, the active component significantly reduced the serum lipid concentration or hepatic cholesterol levels in hyperlipidemia rats, when administrated at oral dosages of 300 mg/ kg/ day for 4 weeks or injected intraperitoneally at 50 mg/ kg/ day for 30 days( Yan et al ., 2006 ). Furthermore, hepatic lipid metabolism was also enhanced in ovariectomized rats by oral administration of Kudzu root( Wang et al ., 2004 ).

Reynoutria japonica Houtt( Polygonaceae)

Reynoutria japonica Houtt is a synonym of Polygonum cuspidatum siebold and Zucc. Its dried root and rhizome is known as Huzhang in Chinese medicine. Polydatin and resveratrol are the main active components. It has been found that oral administration of polydatin at dosages of 25 mg-1 50 mg/ kg/ day for 15 -2 1 days significantly decreased TC, TG, and LDL-C levels or TC/ HDL-C ratio in hyperlipidemic hamsters or rabbits( Du et al ., 2009; Xing et al ., 2009 ). Intragastrical administration of another component resveratrol at dosages of 10-70 mg/ kg/ day for 6 weeks not only decreased high levels of serum lipid but also attenuated diet-induced hepatic steatosis and atherosclerosis index in hyperlipidemic mouse( Xie et al ., 2014 ).

Rheum palmatum Linn( Polygonaceae)

Rheum palmatum Linn ., Rheum tanguticum Maxim. Ex Balf ., or Rheum officinale Baill belongs to the family of Poygonaceae. Radix Et. Rhizoma Rhei, also known as Dahuang or rhubarb, is derived from the root and rhizome of Polygonaceae members. The main active component includes rhein, aloe emodin, emodin, chrysophanol, and physcion. There is a series of studies exhibited the lipid-lowering consequences in animals or patients. For instance, the decoction simmered from rhubarb at 8, 16, and 32 g/ kg/ day for 5 days caused fatty degeneration of the hepatic cell in mouse. Administration of the powders of rhubarb, at 5 g/ day orally for 24 weeks, decreased serum TG and TC levels in patients with diabetic nephropathy( Gao Q. et al ., 2010 ). Rhein, one of the active components or rhubarb, at an oral dosage of 150 mg/ kg/ day for 12 weeks, was proved to be lowering serum TG, TC, and LDL-C levels in mouse with diabetic nephropathy. Thus the lipid-lowering effect of rhubarb, at least, partially dues to the component rhein. Danthron is another extract of rhubarb. It was observed that danthron dose-dependently promoted the phosphorylation of AMPK and acetyl-CoA carboxylase in both HepG2 and C2C12 cells. Meanwhile, danthron significantly reduced sterol regulatory element-binding protein 1c synthesis and fatty acid synthase gene expressions, make contributions to the inhibitory impact on lipid metabolism( Han et al ., 2013 ). However, some side-effects, including retch, headache, diarrhea and abdominal ache, are reported by some volunteers.

Salviae miltiorrhizae( Lamiaceae)

It has been described in Section” Application of Plant Products in Hypertension .” It is widely used to treat patients with coronary artery cancer in China. Examines have demonstrated decrement in high levels of TC, TG and LDL-C when administrated with its aqueous extracts orally( 50, 100, and 150 mg/ kg/ day for 4 weeks in hyperlipidemic rats)( Ji and Gong, 2008) or intravenous injected with tanshinone IIA, the main component (8 0 mg/ day for 14 days in patients with diabetes)( Jang et al ., 2008 ).

Scutellaria baicalensis Georgi( Lamiaceae)

Scutellaria baicalensis, known as Huangqin, is derived from the dried root of Scutellaria baicalensis Georgi. The most effective lipid-lowering component is flavonoid compound. Both stem-leaf total flavonoids administrated at oral dosages( 25 -1 50 mg/ kg/ day) and 0.05% radix extract added to the diet significantly reduced the serum TG, TC, and LDL-C levels or increased HDL-C levels( Regulska-Ilow et al ., 2004 ). In addition, therapy with flavonoids from the Huangqin leaves increased the activity of lecithin cholesterol acyltransferase in hyperlipidemia rats( Regulska-Ilow et al ., 2004 ), make contributions to the lipid-lowering effect.

Senna obtusifolia Linn.( Fabaceae) or Cassia tora Linn.( Leguminosae)

The ripe seed of Senna obtusifolia Linn.( Fabaceae) or Cassia tora Linn.( Leguminosae) is Semen Cassia, known as Juemingzi. Anthraquinone glycosides are the active component. It has been found that the extract from Semen Cassia at lower doses (8 -1 5 mg/ kg/ day) for 35 days, or at highest dose( 180 mg/ kg/ day) for 7 days, significantly decreased TC, TG and LDL-C and increased HDL-C in hyperlipidemic animal models. Similar outcomes were induced by administration with the total anthraquinone from Semen Cassia for 2 months in alcohol treated SD rats( Guo et al ., 2014 ).

The Others

There are many other herbs which demonstrate the hypolipidemic consequences and widely used in Chinese medicine. These herbs include Rhizoma( Chuanxiong ), Rhizoma Curcumae Longae( Jianghuang ), Rhizoma Alismatis( Zexie ), Semen Plantaginis( Cheqianzi ), and Folium Nelumbinis( Heye ). The oral administration of the extracts or the active components exerts the hypolipidemic consequences and improving lipid metabolism( Guo et al ., 2014 ). In addition, there are some formulae for dyslipidemia which are applied in clinic basing on syndrome differentiation( China Association of Chinese Medicine, 2008 ). The formulae are listed in Table 2.

Application of Plant Products in Heart Diseases

Cardiovascular cancers involving the heart includes angina, myocardial infarction, cardiomyopathy, congenital heart disease, and heart failure, etc. Some of the diseases interact on one another or on other vascular cancers. For instance, coronary artery cancers involve atherosclerosis, which may be caused by hypertension, hyperlipidemia, whereas heart failure can start as consequence of large myocardial infarctions. Thus, herbs is used in therapy of hypertension, atherosclerosis and lowering lipid profiles should contribute to attenuating heart diseases too. Here, we present formulae and the natural plants frequently used in clinic and lab examines in alphabetical order.

Formulae

There are some formulae which are frequently used to treat heart diseases. Chinese herbal formula Sini Tang/ dicoction( Aconitum carmichaelii, Zingiber officinale, Glycyrrhiza uralensis, or/ and Cinnamomum cassia) was reported to improve cardiac function( ejection fraction and fractional shorten) after myocardial infarction in rats. With 1H NMR and UHPLC-MS measurement, 21 -day be applied in Sini decoction effectively reversed the urinary metabolic profiles in the myocardial infarction rat model( Tan et al ., 2012; Sheu et al ., 2014 ). Another formula consists of Terminalia arjuna, Cactus grandiflorous, Crataegus oxyacantha, and Piper nigrum. Preadministration and postadministration of this herbal mixture restore high levels of biomarker of cardiotoxicity, including cardiac marker enzymes, lipids profile, and antioxidant enzymes( Lin et al ., 2011 ). Rhodiola formulation is claimed to relieve the symptoms of ischemic heart disease and improve the electrocardiography in a number of clinical examines( Yu et al ., 2014 ). A meta analysis including 13 examines( n= 1672) demonstrated that the efficiency of Rhodiola formulations was higher compared to control group( symptoms improvement: OR= 2.40, 95% CI: 1.57 -3. 66, P <0.0001; electrocardiography improvement: or = 1.48, 95% ci: 1.17-1.87, p <0.01). in addition, the ors of symptomatic and electrocardiography improvement in rhodiola formulations versus other chms, versus routine western medicine, and rhodiola formulations plus routine western medicine versus routine western medicine were 1.51, 2.64, 5.63, and 1.33, 3.11, 2.27, respectively (yu et al., 2014). these findings indicate that the formulations have a positive effect on treating ischemic heart disease alone or in combination with routine western medicine. in addition, there are some formulae for angina pectoris or coronary heart disease or heart failure which are based on syndrome differentiation (china association of chinese medicine, 2008) and are listed in tables 3 and 4.

Astragalus propinquus (Leguminosae, Fabaceae)

Injection of Astragalus, also known as Huangqi, is one of the most commonly used Chinese patent medicines for the treatment of chronic heart failure in China as complementary treatment to recommended Western therapies. Fu et al. (2011) has reviewed 62 clinic trials from 1205 articles. Although the available studies are not adequate to draw a conclusion on the efficacy of the Huangqi injection, it is observed to enhance myocardial contractility, improve circulation, and protect myocardial cells with modern pharmacological tools. For example, in an in vivo rat model of persistent myocardial ischemia produced by occlusion of the left anterior descending coronary artery, pretreatment of Huangqi extract significantly decreased the myocardial infarct size and the serum levels of lactate dehydrogenase, creatine kinase isoform MB, and cardiac troponin. Additionally, this treatment dramatically improved cardiac function, as assessed by dP/dt, left ventricular developed pressure, and left ventricular end-diastolic pressure (Ma et al., 2013).

Cecropia pachystachya (Urticaceae)

Cecropia pachystachya, popularly called ambay, is extensively used in herbal medicine of South America. Cecropia pachystachya Mart growing in a temperate region produced a positive inotropic effect on isolated rat hearts independent of beta-adrenergic effect. In contrast, the inotropic effect was prevented by pretreatment with high potassium media (stimulating Na-K-ATP pump), indicating an inhibition of the pump by ambay (Consolini et al., 2006).

Crataegus spp. (Rosaceae)

It has been described in previous sections (hawthorn). In isolated perfused hearts, extracts of hawthorn have been reported to show cardioprotective effects without affecting coronary blood flow (Nasa et al., 1993). Simultaneously, they demonstrated vasodilator actions and positive cardiac inotropic effect (Blesken, 1992). These results were verified in a multicenter, placebo-controlled, double-blind study, in which WS 1442, the special extract of hawthorn, improved cardiac function determined by heart rate product (systolic BP A heart rate) in patients with NYHA class II heart failure( Weikl et al ., 1996 ). More examines are needed to investigate the mechanisms of hawthorn to attenuate CVDs.

Olea europaea L.( Oleaceae)

It has been described in previous sections and the main extract from the olive leaves is oleuropein. The rabbits were subjected to a 30 min period of regional ischemia of the heart followed by a 3 h reperfusion. Chronic pretreatment with oleuropein reduced the infarct size in comparison with the control( Andreadou et al ., 2006 ). In doxorubicin-induced cardiomyopathy, oleuropein effectively improved the impaired cardiac geometry and function provide evidence of transthoracic echocardiography( Andreadou et al ., 2014 ). In isolated rat hearts, pretreatment with 20 I1/ 4g/ g oleuropein before ischemia resulted in a significant decrease in creatine kinase and reduced glutathione release in the perfusate. Reflow in ischemic hearts induced oxidized glutathione release and membrane lipid peroxidation, which were help prevent oleuropein. The reported data demonstrated the direct cardioprotective effect of oleuropein in the acute events that are consistent with coronary occlusion, and the nutritional benefit of olive oil in the prevention of coronary heart disease( Weikl et al ., 1996 ).

Panax notoginseng( Araliaceae)

The root of Panax notoginseng, known as Sanqi, Sanchi or Tianqi in East Asian countries, has been identified over 80 variants according to different substitute patterns. There are five main saponins R1, Rb1, Rg1, Rd, and Re, constituting up to 90% of the total Panax notoginseng used in the pharmacological experiment. A myriad of studies demonstrate the protective effect of notoginseng in cardiac injury. Firstly, it could significantly improve rats’ cardiac function provide evidence of left ventricular ejection fractions, left ventricular fractional shorten, left ventricular dimensions at end diastole and left ventricular dimensions at end systole( Chen et al ., 2011 ). Secondly, it could reduce infarct size and serum level of creatine kinase in rat models of myocardial ischemia( Yue et al ., 2012; Han et al ., 2013 ). Thirdly, it decreased serum high levels of lactate dehydrogenase, cardiac troponin I, malondialdehyde and several cytokines, including TNF-a, IL-1I 2 and C-reactive protein( Han et al ., 2013 ). These findings indicate considerable therapeutic potentials of notoginseng for myocardial infarction. Interestingly, Notoginseng combined with the powdered extract of Carthamus tinctorius, an anti-thrombus herbal medicine, or with Sals, the active ingredient of C. tinctorius, demonstrated stronger consequences to reduce infarct size than either narcotic alone( Yue et al ., 2012; Han et al ., 2013; Liu et al ., 2014 ). Thus, combining drug remedy should be considered for CVDs treatment.

Salviae miltiorrhizae( Lamiaceae)

In addition to hypertension and hyperlipidemia, the dried root of Salviae miltiorrhizae( Danshen) is widely used in China for the therapy of angina pectoris and acute ischemic stroke. It has a range of potentially beneficial effects, including improving microcirculation, causing coronary vasodilatation, repressing the formation of thromboxane, hindering platelet adhesion and aggregation, and protecting against myocardial ischemia. Danshen is widely used either alone or in combination with other herbal ingredients for patients with coronary artery cancer or CVDs. An acute myocardial infarction model was induced and both infarct size and echocardiographic reaction were evaluated at different day after surgery. Both Sal and tanshinone( two hypdrophilic and lipophilic compounds) delayed the development of ischemia by lessening infarct size and improving systolic function post myocardial infarction( Wang et al ., 2011 ). However, a recent its consideration of randomized controlled trials of Danshen in ischemic cancer published in mainland China identified 150 trials from 1998 to 2007, but concluded that the quality of these trials has not improved significantly over recent years and the overall quality is still poor( Yu et al ., 2014 ). Since clinical examines have various methodological problems, further high-quality randomized controlled trials should be performed to assess the efficacy of this herb.

Mechanisms of Plant Products in the Attenuation of CVDs

For over 2000 years, CVDs have been treated with numerous herbal remedies. However, these herbal remedies have not been well studied using modern cellular and molecular techniques. Based on the existing investigations into the system of single herbal compounds, a summing-up of these studies is presented in the following point wherein the compounds are discussed according to their target site of activity.

Vascular Smooth Muscle Cells

Inhibiting Expression or Activity of Contractile and Structural Proteins

The blood vessel tonicity is principally controlled by the contraction and relaxation of VSMCs. Upon stimulation, smooth muscle cells develop a contractile force by using the cross-bridge cycling between the contractile proteins actins and myosin initiated by the Ca2+ -calmodulin interaction and modulated by many other proteins. Herbal medicine that governs proteins or molecules in this pathway would modulate vascular contraction or relaxation. Firstly, blocking contractile and structural proteins may be one of the ways which natural plants could facilitate vasodilation and vascular remodel. It has been shown that Tianma( the tuber of an orchid) improves acetylcholine-induced vasorelaxation or phenylephrine-induced contraction in aortic rings( Feng et al ., 2012 ). In more details, long-term therapy with small dosages of Tianma resulted in a significant decrease of the expression high levels of primary contractile protein actin to about half the level of the controls, as well as other cytoplasmic structural/ cytoskeletal proteins, like Des, Vcl, Pdlim1 and Map4. Secondly, phosphorylation of myosin lighting chain protein is another target for herbs to determine vascular smooth muscle contraction. A10 cells, rat smooth muscle cells, were treated with kinds of herbs and it was observed that four herbs, Liu-Wei-Di-Huang-Wan, Jia-Wei-Xiao-Yao-San, Danshen and Gegen, reduced phosphorylation of myosin lighting chain, suggesting that these most common herbs may be beneficial for smooth muscle cell contractility( Lin et al ., 2015 ).

Regulating Expression of Extracellular Matrix Proteins

Extracellular matrix is another target involved in vascular tone regulation. ECM proteins such as Postn is specifically induced upon tissue injury and could promote cellular adhesion and motion as well as collagen fibrillogenesis. ECM glycoproteins include Eln, Fbln5 and Prelp, being essential to maintain arterial morphogenesis and vessel elasticity. Tianma could induce up-regulation of ECM glycoproteins and down-regulation of ECM proteins in vascular system, thereby regulating blood vessel tonicity by increasing the arterial elasticity and stabilizing the arterial structure( Feng et al ., 2012 ).

Regulating Calcium Levels in PKA/ PKG/ PKC-Dependent Way

Calcium levels in VSMCs also contribute to regulating the vascular contraction. Tetramethylpyrazine( TMP, also known as Ligustrazine ), is a vasoactive component derived from Ligustium Wollichii Franchat. Using dog mesenteric arterial ring preparations, TMP not only caused a dose-dependent inhibition of vascular contractile responses to KCl and phenylephrine in answer with calcium, but also inhibited the responses to phenylephrine in Ca-free medium containing 50 I1/ 4M EGTA. These outcomes suggest that herbs may regulate vascular contraction or relaxation by the inhibition of Ca2+ influx, as well as the release of intracellular calcium( Kwan et al ., 1990 ). Consistent with it, baicalein reduced AngII-, vasopression- and endothelin-stimulated increase in[ Ca2 +] i of VSMCs( Saito et al ., 1992 ). This impact was simulated by a structurally unrelated lipoxygenase inhibitor, 5,8, 11 -eicosatriynoic acid and was restored by addition of 12( S) -hydroxyeicosatetraenoic acids( Saito et al ., 1992 ). Thus, baicalein may be representative of the hypotensive herbs mediating Ca2+ levels which may be partly attributed to its inhibition of lipoxygenase and consequent decrease in biosynthesis and release of arachidonic acid-derived vasoconstrictor products.

Alterations in large-conductance Ca2+ -activated K+ channel( BKCa channel) activity play a central role in mediating vasoconstriction and vasodilation. Baicalin( 10 -1 00 I1/ 4M) not only concentration-dependently attenuated KCl-contracted mesenteric arteries, but also abolished selective BKCa-channel inhibitor IbTX, voltage-dependent Ca2+ channel activator BayK8 644, and PKC activator PM-Ainduced contractions at concentrations of 100 I1/ 4M( Lin et al ., 2010 ). These findings suggested that baicalin relaxes mesenteric artery via modulation of the BKCa and Ca2+ channels which may be mediated by the PKC associated pathway. Then, the BKCa-mediated vascular contraction is further explored. The camp and the cGMP pathways are major regulators of smooth muscle contractility. By cyclic nucleotide assays, baicalin enhanced both camp and cGMP levels in mesenteric arteries. Based on the hypothesi that smooth muscle relaxants that increase camp and cGMP have been shown to activate BKCa channels through direct phosphorylation of the channel proteins and through elevation of Ca2+ spark frequency, Lin et al.( 2010) measured the effects of baicalin on BKCa current by whole-cell patch clamp electrophysiology. Baicalin was observed to enhance BKCa currents in a concentration-dependent manner, which were abolished by blending inhibitors of AC( SQ 22536) and sGC( ODQ ), by blending inhibitors of PKA( KT5720) and PKG( KT5823 ), and PKC activator( PMA) in mesenteric artery smooth muscle cells. These outcomes indicate that baicalin-induced mesenteric artery relaxations could be due to BKCa channel activating occurs not only as a result of PKA and PKG, but also as a result of cross-interaction with PKC( Lin et al ., 2010 ).

Attenuating Proliferation and Migration of VSMCs

It’s well known that stimulation of VSMCs with TNF-I +- or platelet-derived growth factor-BB induced proliferation. Camellia japonica at concentrations 50, 100, 200, and 400 I1/ 4g/ mL significantly reduced the proliferation rate to 77.85, 70.12, 61.93, and 56.33% of the control( TNF-I +- treated without Camellia japonica)( Park et al ., 2015 ). Similarly, Cinnamon extract inhibited the platelet-derived growth factor-BB-induced proliferation of VSMCs through a G0/ G1 apprehend, which down-regulated the expression of cell cycle positive regulatory proteins by up-regulating p21 and p27 expression( Kwon et al ., 2015 ). The effects of Camellia japonica on VSMCs migration was assessed with a meander mending assay. Camellia japonica concentration-dependently suppressed platelet-derived growth factor-BB induced VSMCs wound mending for 24 and 48 h after injury, indicating the migration hindering consequences( Park et al ., 2015 ). In addition, baicalein and baicalin induced anti-proliferative and anti-mitogenic consequences in VSMCs of rabbit, rat and bovine were well summarized( Huang et al ., 2005 ). These outcomes offer additional proof for the beneficial cardiovascular effects of natural products.

Anti-inflammation

Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used as an anti-inflammatory narcotics in Asia. The the system of the inflammatory effects of andrographolide in VSMCs were investigated by exposing VSMCs to a proinflammatory stimulus, TNF-I +-. Treating TNF-I +- -stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase( NOS ), JNK, Akt, and p65 phosphorylation. However, it demonstrated no effect on either IIoBI +- degradation or p38 mitogen-activated protein kinase or ERK1/ 2 phosphorylation under these conditions. Both therapy with LY294002, a phosphatidylinositol 3-kinase/ Akt inhibitor, and therapy with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. Thus, andrographolide-mediated inhibition of NF-IoB activity in TNF-I +- -stimulated VSMCs occurs through the JNK-Akt-p6 5 signaling cascade mechanism, which is independent of IIoBI +- degradation( Chen et al ., 2014 ). These outcomes collectively suggest that therapeutic interventions utilizing andrographolide can benefit the therapy of vascular inflammatory diseases.

Improving Mitochondrial Function

In addition to cellular powerhouses, mitochondria are known as critical regulators of cell demise. And they are the major cellular source of ROS which causes damage to mitochondrial DNA in human VSMCs in a number of cardiovascular pathologies. Thus, mitochondrial dysfunction may lead to the impairment of various aspects of tissue operate. It has been known that cultured rat aortic VSMCs treated with AngII for 24 h exhibited mitochondrial dysfunction, including a decrease in mitochondrial oxygen consumption rates, ATP production and mtDNA levels, as well as the interruption of mitochondrial structural integrity( Lu et al ., 2015 ). Together with the mitochondrial morphological changes, these modifications were reversed by Astragaloside IV, the major active ingredient of Astragalus membranaceus( Fisch .) Bge.( a traditional CHM ). Moreover, therapy with Astragaloside IV also reversed the AngII-induced increase in the production of ROS, the increasing number of NADPH oxidase and xanthine oxidase activity, as well as the decrease in mitochondrial membrane potential and manganese-SOD activity. Furthermore, therapy with Astragaloside IV led to an increase in the mRNA and/ or protein high levels of peroxisome proliferator-activated receptor-gamma coactivator-1I +-( PGC-1I +-), mitochondrial transcription factor A, parkin and dynamin1-like protein1 in the VSMCs. These outcomes indicate that Astragaloside IV exerts beneficial effects on AngII-induced mitochondrial dysfunction in rat VSMCs and that these effects are mediated through the inhibition of ROS overproduction, as well as the promotion of mitochondrial autophagy and mitochondrial biogenesis( Lu et al ., 2015 ).

Overall, herbal medicines discussed here do appear to show pharmacological consequences in vitro and in animal examines, which may influence CVDs. In VSMCs, these natural plants exert the protective impact by a series of process( Figure 1) which include inhibiting expression or activity of contractile and structural proteins, modulating expression of ECM proteins/ glycoproteins, regulating calcium levels, attenuating proliferation and migrations, alleviating inflammation, and improving mitochondrial function.

Endothelial Cells

Activation of NO Signaling Pathway

Endothelial cells, which constitute the inner cellular lining of blood vessels, have a key role in regulating vascular homeostasis and function, such as vasorelaxation, vascular integrity, and local inflammation. Endothelium-dependent vasodilation was usually applied to examine the endothelium function, in which NO is a potent vasodilator and plays an important role in regulating vascular tones. Some herbal medicine functions by targeting at the NO making process. In examines at the arterial levels, both Lysimachia clethroides and gypenosides elicit vasorelaxation which was abolished by endothelial NOS( eNOS) or guanylyl cyclase inhibitors( Tanner et al ., 1999; Lee et al ., 2010 ). Sal B, a hydrophilic caffeic acid derivative of Danshen, exerts an important regulatory function on endothelial tissue of isolated mouse aorta by promoting NO production through the inhibition of arginase activity( Joe et al ., 2012 ). Fo Shou San, an ancient herbal decoction( Chuanxiong Rhizoma and Angelicae Sinensis Radix Danggui in a ratio of 2:3 ), reversed homocysteine-induced impairment of acetylcholine-evoked endothelium-dependent relaxation in rat aortic rings( Bi et al ., 2012 ). In examines at the cellular levels, gypenosides induced a concentration-dependent increase in NO production from cultured bovine endothelial cells( Tanner et al ., 1999 ). Consistent with it, magnesium tanshinoate B( another compound purified from Danshen) or Fo Shou San, also induced the release of NO and its metabolites from a human endothelial cell line( ECV3 04)( O et al ., 2000; Bi et al ., 2012 ). By exploring the mechanisms by which NO production is induced, it was observed that the cellular NOS activities were significantly enhanced with a concomitant increase in high levels of constitutive NOS protein mass( O et al ., 2000 ), phosphorylation levels of serine1 177 -eNOS and serine4 73 -Akt( Lee et al ., 2010; Lu et al ., 2010; Bi et al ., 2012) by a series of herbal products therapy, including magnesium tanshinoate B, lysimachia clethroides , nordihydroguaiaretic acid( main metabolites of creosote shrub) and Fo Shou San. In addition, Fo Shou San elevated intracellular Ca2+ levels and eNOS phosphorylation, which was inhibited by the Ca2+ chelator BAPT-AAM( Bi et al ., 2012 ). These outcomes indicate herbals may benefit endothelial function through increased activity of Akt kinase and eNOS, which is via a rise of intracellular Ca2 +.

Inhibition of Inflammation

Inflammation plays a crucial role in the pathophysiology of CVDs, in which adhesion molecules, pro-inflammatory cytokines and chemokines are involved. The anti-inflammatory effects of Danshen and its active ingredients( Sal B, Tanshionone IIA, Protoc et al .) were extensively investigated in traditional Chinese medicine for therapy of CVDs. Incubation with TNFI +- or ADP is widely used to induce inflammation in vitro. In TNFI +- treated human coronary artery endothelial cells, Sal B significantly impeded the inflammation and decreased matrix metalloproteinase-9 expression and activity by blocking the activation of IIoBI +-/ NFIoB through JNK and ERK1/ 2 signaling pathways( Ma et al ., 2015 ). In TNFI +- treated HUVECs, although neither Sal B nor Tanshinone IIA impede the inflammation( Stumpf et al ., 2013 ), Danshen and Protoc attenuated expression and/ or release of CD40, VCAM-1 and ICAM-1 as well as cytokines or chemokines( IL-6, IL-8 and MCP-1)( Stumpf et al ., 2013 ). In ADP-treated human platelets, pre-treatment with both Sal B, Tanshionone IIA and Danshen significantly attenuated platelet P-selectin expression( Stumpf et al ., 2013 ). Gypenoside XLIX, a dammarane-type glycoside, is a prominent component of G. pentaphyllum. Studies demonstrate that Gypenoside XLIX inhibits TNFI +- -induced VCAM-1 over expression and hyperactivity in human endothelial cells via a PPARI +- -dependent pathway( Huang et al ., 2007 a ). These findings provide useful insight into the rational basis of CHM in the treatment of CVDs.

Attenuation of Oxidative Stress

It’s well known that oxidative stress contributes to endothelium dysfunction. There are a myriad of herbs that demonstrate effects of endothelial cell protection by different mechanisms. For instance, Sal B lessens ROS production in the aortic rings. Since ROS easily acts with NO to produce peroxynitrite anions, which is a potent and potentially toxic oxidant that injuries various types of biomolecules, it can be deduced that Sal B may exert its protective function by foreclosing NO consumption through adverse reactions such as peroxynitrite formation and preserving NO bioavailability( Joe et al ., 2012 ). EGb 761( Ginkgo biloba extract) squelches oxidative stress in a dose-dependent manner in high glucose-stimulated HUVEC. In addition to inhibition of ROS generation and 8-OHdG content, it attenuated oxidative DNA damage, indicating herbs could exert endothelial protection by alleviating endothelial DNA oxidation( He Y.T. et al ., 2014 ). Echium amoenum extract( an important source of anthocyanins) demonstrated antioxidant and cytoprotective impact in H2O2-treated HUVECs. In the endothelial injury model, pretreatment of HUVECs with the anthocyanin-rich extract at concentrations of 100-1000 I1/ 4g/ ml reduced the cell demise, decreased hydro peroxide concentration, and increased ferric reducing antioxidant power value in both intra- and extra-cellular liquid in a concentration-dependent manner( Safaeian et al ., 2015 ). KRGE reduces the H2O2-induced cell injury in HUVECs too. The inhibited impact on cell demise was blunted by HO-1 inhibitor zinc protoporphyrin. HO-1 is considered to augment the cellular defense against various agents inducing cytotoxic injury. KRGE was observed to induce up-regulation of HO-1 expression in HUVECs, which was abolished by specific silencing of Nuclear factor-eythroid 2-related factor 2( Nrf2, a important anti-oxidant transcription factor) expression( Yang et al ., 2011 ). These outcomes suggest that Korean Red Ginseng may exert a vascular protective impact through Nrf2-mediated HO-1 induction in human endothelial cells. Ophiopogonin D is one of the most bioactive components of Radix Ophiopogon japonicas. Its pretreatment demonstrated a series of antioxidation-related protective consequences:( 1) reducing H2O2-induced lipid peroxidation and protein carbonylation,( 2) attenuating mitochondrial ROS generation and cell apoptosis,( 3) restoring cellular total antiboidative capacity,( 4) hindering the release of inflammatory cytokines and blocking activating of NFIoB and ERK signaling cascades,( 5) repressing the enzymatic activity of catalase, HO-1, and caspases( Qian et al ., 2010 ). In general, these findings support the protective role of herbs as an effective antioxidant in endothelial injury.

Inhibition of Apoptosis

Although endothelial cell dysfunction occurs in many different cancer processes, caspase-dependent apoptotic cell demise induced by the extrinsic or intrinsic pathways is identified as a common denominator. Protective effect of KRGE was examined in a serum-deprived apoptosis model, which demonstrated that it could avoid serum deprivation-induced HUVEC apoptosis( Kim et al ., 2013 ). This impact was mediated by increased Bcl-2 and Bcl-XL protein expression, PI3K/ Akt-dependent Bad phosphorylation, and eNOS/ NO-mediated S-nitrosylation of caspases. Cytosolic cytochrome c is known to play a crucial role in the activation of the initiator caspase-9 and the effector caspase-3. KRGE avoided subcellular redistribution of cytochrome c from the mitochondrion into the cytosol, resulting in suppression of the extrinsic pathway of apoptosis activation( Kim et al ., 2013 ). The cytoprotective property of KRGE may be valuable for developing new pharmaceutical means that limit endothelial cell demise induced during the pathogenesis of vascular diseases.

Inducing Angiogenesis

Angiogenesis, the formation of new blood vessels from preexisting endothelium, is critical to a variety of process, both physiologically( embryonic growth and wound mending) and pathologically( malignancy and chronic inflammation ). It is a complex biologic function comprising several steps, including sequential basement membrane degradation, endothelial cell migration and proliferation, tube formation, inhibition of endothelial proliferation, and the stabilization of new ships. Modulation of any of these steps would affect new vessel formation. Scutellarin, a known flavone glycoside, is the primary active component of the traditional CHM Erigeron breviscapus( Vant .) Hand. Mazz. It has been shown to induce endothelial cell proliferation and migration, promote capillary-like tube formation, and significantly upregulate platelet endothelial cell adhesion molecule-1( Gao Z.X. et al ., 2010 ). These outcomes suggest that herbal medicine promotes angiogenesis and may form a basis for angiogenic therapy.

Suppression of Endothelial Permeability

Endothelial cell hyperpermeability is another factor implicated in CVDs, in which the importance of tyrosine phosphorylaton and kinase activity in oxidant-mediated loss of cell junction structures has been demonstrated. Extract of salvia miltiorrhiza and its major ingredients, Danshensu and Sal B impeded TNFI +- -induced endothelial permeability, provide evidence of attenuated junctional protein phosphotyrosine and prevention of beta-catenin disassociation from the cytoskeleton( Ding and Yuan, 2007 ). The mechanism of pharmacological action was further explored. The extract, Danshensu and Sal B also repressed expression of vascular endothelial growth factor and ERK activation in TNFI +- treated HUVEC cells. In addition, it was found that the extract attenuated the disorganization of vascular endothelial-cadherin, which is likely due to a reduction of vascular endothelial growth factor protein expression as a result of modulation of the ERK signaling pathway( Ding et al ., 2005 ). These findings suggest that active herbal ingredients may help to attenuate CVDs by maintaining the integrity of endothelial junction structure.

In general, herbal medicines do demonstrate the beneficial effects in endothelial cells. As shown in Figure 1, these natural plants exert the protective impact by inhibition of inflammation, oxidative stress and apoptosis, activating of eNOS-NO signaling pathway, induction of angiogenesis and suppression of endothelial permeability.

Cardiomyocytes

Alleviation of Cardiac Hypertrophy

Pathological cardiac hypertrophy induced by increased sympathetic drive can subsequently lead to congestive heart failure, which represents the major cause of morbidity and mortality worldwide. Astragalus polysaccharide is an active compound removed from Chinese herb Astragalus membranaceus for “Qi-invigorating.” In the in vitro cardiac hypertrophic model induced by isoprenaline, Astragalus polysaccharide therapy impeded significant increases in cell surface area, total protein content, protein synthesis as well as the expression of hypertrophic markers, including ANP and B-type natriuretic peptide. In addition, Astragalus polysaccharide pretreatment not only alleviated the augmentation of intracellular free calcium during cardiac hypertrophy but also upregulated expression of calcineurin, translocation of nuclear factor of activated T cells, cytoplasmic 3 into nucleus and activating of calmodulin kinase II( reflected by p-CaMKII)( Dai et al ., 2014 ). According to this research, Astragalus polysaccharide exerted its anti-hypertrophic action via hindering Ca2+ -mediated calcineurin/ NFATc3 and CaMKII signaling cascades, which provided new insights into the application of Astragalus polysaccharide to the therapy of heart diseases.

Chlorogenic acid is an important component of CHM, which acts as an antioxidant scavenging free radicals and avoiding inflammation. Pre-treatment of chlorogenic acid in the isoprenaline-induced neonatal rat myocytes, decreased high levels of the hypertrophic markers, ANP, B-type natriuretic peptide and I2-MHC. The level of the intracellular ROS was reduced and the nuclear translocation of NF-IoB was blocked, whereas NF-IoBIA, an inhibitor of NF-IoB, was upregulated accordingly. These data reveal that chlorogenic acid may impede cardiac hypertrophy by attenuating NF-IoB signaling pathway and repressing ROS production( Li et al ., 2014 ).

Attenuation of Oxidative Stress

Many data have demonstrated that ROS production by myocardial endothelial mitochondria contributes to heart disease and oxidative stress within ventricular myocytes can also be detrimental to the heart. In fact, much of the contractile dysfunction and adverse myocardial remodel, which has been observed in a wide range of cardiomyopathies, involves oxidative stress and eNOS uncoupling leading to a decrease in NO. There are a series of targets at which herbal medicine act to improve myocardial endothelial function by attenuation of oxidative stress.

( 1) Intracellular generation of ROS, including superoxide, hydrogen peroxide and hydroxyl revolutionaries, contributes to the pathogenesis of cellular injury during ischemia and reperfusion in cardiac tissues. Thus, free radical scavenging and inhibition of oxidases will exert protective impact in cardiac injury. Baicalein may provide such therapy by deletion of free radicals, reducing hydroxyl revolutionaries generation by suppressing iron-catalyzed Fenton reaction or lessening ROS production by hindering activities of NADH-oxidase and xanthine oxidase( Huang et al ., 2005 ).( 2) ROS may reduce NO bioactivity through the formation of peroxynitrite and NOx. Thus it is easy to understand the oxidized LDLs-induced endothelial dysfunction could be restored by L-arginine and NO. The olive products constitute a rich source of polyphenols such as oleuropein and its derivatives, including hydroxytyrosol, which scavenge free radicals and impede the chemical oxidation of LDL. Studies have shown that therapy with high dosages of oleuropein at min 1 of reperfusion significantly reduced levels in plasma NOx in hypercholesterolemic rabbits coupled with reduction of infarct size in this group( Andreadou et al ., 2014 ). Therefore, plant products may function as a NO donor to impede formation of peroxynitrite and NOx.( 3) Disseminate or cellular high levels of malonaldehyde, TBARS, and protein content in carbonyls serve as Lipid peroxidation and general oxidative stress. The decrease in these biomarkers indicates the protective action of oleuropein, baicalein, crocetin, Allium chinense and Astragalus against oxidative stress by scavenging free radicals( Nasa et al ., 1993; Huang et al ., 2005; Shen and Qian, 2006; Ren et al ., 2010; Andreadou et al ., 2014 ).( 4) A great sum of ROS generates from mitochondrial electron transport inhibition, which induces lethal oxidant damage of cardiomyocytes. Qian-Kun-Nin, a CHM formulation was observed to significantly decreased cell demise and attenuate oxidation of DCFH in cells exposed to the mitochondrial site III inhibitor, antimycin A, consistent with a decrease in oxidative stress( Shao et al ., 2001 ). These findings indicate herbal medicine may impede oxidative stress by improving mitochondrial function.( 5) Myocardial SOD, glutathione peroxidase and myocardial catalase are the main antioxidant enzymes, which are dramatically reduced after ischemia and reperfusion. Pretreatment with oleuropein, Astragalus, crocetin or cynaroside kept the SOD activity stable in myocardial infarction models or norepinephrine induced cardiac hypertrophy and therefore left the myocardium in an” antioxidant nation “( Nasa et al ., 1993; Shen and Qian, 2006; Sun et al ., 2011; Andreadou et al ., 2014 ). Thus, maintaining the function of antioxidant enzymes standards for another target to impede oxidative stress and protect cardiac injury.( 6) Nrf2 is a master transcription factor of endogenous anti-oxidative defense systems. Herbs such as American ginseng could enhance this antioxidant system in rat cardiac H9C2 cells( Li et al ., 2010 ). The antioxidant systems include Nrf2 protein expression, Nrf2 nuclear translocation, Nrf2 transcriptional activity, direct Nrf2 bind to its target gene promoters, and expression of a group of anti-oxidative genes. Thus, herbs may serve as antioxidant enhancer to provide cardioprotection against pathological cardiac injury and remodel.( 7) Doxorubicin triggered impaired left ventricular contractility and inflammatory and degenerative pathology lesions, indicating a successful cardiomyopathy model. Metabonomic analysis revealed therapy of oleuropein induced an favorable variations in the ratio of glycolytic end product( alamine+ lactate) to end products of lipid metabolism( acetate ), suggesting restoration of the impairment in aerobic glucose metabolism and cardioprotection of ischemia( Andreadou et al ., 2014 ). This may help indentifying novel therapeutic targets in the effect of plant products to protect the heart from injury.

Inhibition of Apoptosis

H2O 2 therapy induces both oxidative damage and apoptosis, contributing to cardiac injury in cultured rat cardiomyocytes. Cynaroside, a flavonoid compound, has been shown to enhance the endogenous anti-oxidative activity, thereby hindering intracellular ROS generation. It also demonstrated the protective consequences against H2O2-induced apoptosis in H9c2 rat cardiomyoblasts. The mechanism by which cynaroside reduced the apoptotic rate were further explored. Cynaroside pretreatment not only moderated H2O2-induced disruption of mitochondrial membrane potential, but also increased the expression of anti-apoptotic protein Bcl-2 while decreased the expression of pro-apoptotic protein Bax, and thereby impeded the release of apoptogenic factors( cytochrome c and smac/ Diablo) from mitochondria in H9c2 cells. Moreover, cynaroside pretreatment demonstrated an inhibitory impact on the H2O2-induced increase in JNK and P53 protein expression( Sun et al ., 2011 ). These findings suggest that flavonoid products avoid cardiomyocytes apoptosis in vitro by reducing the endogenous production of ROS, maintaining mitochondrial function, and modulating the JNK and P53 pathways.

Opening KATP Channels

Cardiac myocyte is the cell types in which KATP channels were originally detected. It is well established that KATP channels are present at high density in the sarcolemma of cardiac myocytes where they link membrane excitability with the cellular bioenergetic nation. The opening of these channels in the heart is believed to mediate ischemic preconditioning, a phenomenon whereby brief periods of ischemia/ reperfusion protect the heart against myocardial infarction. Pinacidil is a potassium channel opener which mediate preconditioning at the beginning of sustained hypoxia by opening of sarcolemmal KATP channels( Budas et al ., 2004 ). Similar to it, Guanxinkang treatment benefit the heart function by increasing mRNA and protein expression of KATP subunits( Kir6. 1, Kir6. 2, SUR2A, SUR2B) in ventricular myocytes( Chen et al ., 2010 ). Keep in line with it, extracts of Astragalus demonstrated its anti-apoptotic impact in H2O2-injured cardiomyocytes only when the KATP channels were open, whereas the protective impact was not observed when the channels were inhibited by the KATP channel blocker( 5-HD, glibenclamide)( Nasa et al ., 1993 ). These findings indicate enhancing the open of KATP channel is one of the important mechanisms by which herbs protect myocardial cells from ischemic injury.

ANP Secretion

Atrial natriuretic peptide is secreted by the heart atrium cells. ANP binds to a specific set of receptors and acts to reduce the water, sodium and adipose loadings on the circulatory system, thereby reducing cardiac output and systemic BP . Emodin, an active anthraquinone constituent isolated from the rhubarb, was observed to increase ANP secretion concomitantly with a decrease in atrial pulsing pressure and stroke volume in a concentration-dependent manner. Inhibition of K+ channels with tetraethylammonium and glibenclamide or inhibition of L-type Ca2+ channels with nifedipine, attenuated the emodin-induced changes in ANP secretion and atrial dynamics( Zhou et al ., 2014 ). These findings demonstrate that emodin may increase ANP secretion via inhibition of L-type Ca2+ channels through an activating of KATP channel in isolated beating rabbit atrium. This examine provides a rationale for the use of herbal medicine in the treatment of impairment of the regulation of the cardiovascular homeostasis.

To summarize, plant products/ herbal medicines do protective cardiomyocytes from injury. As shown in Figure 1, plant products/ herbs demonstrate the beneficial impact by hindering cardiac hypertrophy, oxidative stress and apoptosis, opening KATP channels and increasing ANP secretion.

Macrophages and Monocytes

Inhibition of iNOS-Mediated NO Production

In the milieu of cardiovascular risk factors that disturb vascular homeostasis, inflammation represents a key early event in vascular pathology, in which monocytes activating, adhesion to the endothelium and infiltration of macrophages into blood vessels are thought to play important pathogenic roles in atherosclerosis and other inflammatory CVDs. It’s well known immune cells-derived excessive production of NO by inducible NOS( iNOS) can cause endothelial damage, leading to multiple vascular wall injuries. The transcriptional and translational regulation of iNOS in various cell types can be induced by cytokines, growth factors, and endotoxins. Lipopolysaccharide( LPS) stimulation has been shown to enhance iNOS expression, NO production, and macrophage arginase activity in RAW 264.7 macrophages, which were inhibited by Danshen extracts and Sal B. In addition, cytoprotective molecule HO-1 expression was upregulated by these Danshen products too( Joe et al ., 2012 ). SnPP is well characterized as a potent competitive inhibitor of HO activity. Since the iNOS expression, NO production, and TNFI +- production, were completely abolished by SnPP, the anti-inflammatory effect of Sal B in macrophages may be related to modulation of HO-1. Hb serves as a CO scavenging compound. Preincubation of Hb for 30 min reversed the inhibitory effect of Sal B on LPS-induced iNOS expression, NO production and NFIoB activation in the RAW 264.7, indicating the regulatory effect of Sal B on inflammation may be through mediating the formation of CO( Joe et al ., 2012 ), which shares the similar mechanism to HO-1 down-regulating proinflammatory cytokines production in LPS-stimulated macrophages( Otterbein et al ., 2000 ). Although the mechanism by which HO-1 down-regulates iNOS is incompletely clear, it may involve transcriptional inhibition through CO formation or reduction of heme bioavailability for iNOS synthesis.

Activation of Estrogen Receptor

Consistent with the effect of Sal B, Tanshinone IIA( another major compound removed from Danshen) exerts its anti-inflammatory consequences by inhibition of iNOS gene expression and NO production, as well as inhibition of inflammatory cytokine( IL-1I 2, IL-6 and TNFI +-) expression in RAW 264.7 cells( Fan et al ., 2009 ). Since Tan IIA has a similar structure to that of 17 I2-estradiol, the estrogenic activities was examined in the immune cells. The Tanshinone IIA’s anti-inflammatory consequences was simulated by estradiol and blocked by ICI1 82187, the antagonist of estrogen receptor( Fan et al ., 2009 ). In fact, the most commonly used alternative herbal medicines for estrogen replacing are soy, black cohosh, dong quai and ginseng. Thus, these herbal medicines may serve as a potential selective estrogen receptor modulator to treat inflammation-associated CVDs without increasing the risk of breast cancer.

Activation of PPARI +-

Activation of the nuclear receptor, PPARI +-, has been demonstrated to modulate many aspects of lipoprotein metabolism and inflammation both in vitro as well as in vivo. The tissue distribution of PPARI +- is extensive and it may mediate many of anti-inflammatory and anti-atherogenic consequences. Gypenoside XLIX, a dammarane-type glycoside, is one of the prominent components in Gynostemma pentaphyllum. It has been identified as a potent PPARI +- activator in HUVEC study( Huang et al ., 2007 a ). Tissue factor is involved in many cancers including CVDs and hence may be an attractive target for directed CVDs therapeutics. In human monocytic THP-1 cells transfected with promoter reporter constructs pTF-LUC, Gyp XLIX( 0-300 mM) concentration-dependently impeded LPS-stimulated tissue factor promoter activity, mRNA and protein overexpression. This impact was similar to those of Wy-1 4643, a potent synthetic PPARI +- activator, and completely abolished in the presence of the PPARI +- selective antagonist MK-8 86( Huang et al ., 2007 b ). These data indicate that Gyp XLIX inhibits LPS-induced tissue factor overexpression and enhancement of its activity in human THP-1 monocytic cells via PPARI +- -dependent pathways, new insights into the mechanism of the Chinese herbal plants in CVDs treatment.

Overall, the natural plants/ herbs do demonstrate inhibition of inflammation in macrophages and monocytes. These consequences are achieved by inhibition of iNOS-NO signaling pathway, which may be through activating of estrogen receptor and nuclear receptor PPARI +- -dependent signaling pathways( Figure 1 ).

Conclusion

Although many studies have been missed during its consideration of the report due to our search strategy and the limited access to some articles, the aforementioned proof is strongly indicative of the notion that herbs/ natural plants are the emerging medicine in the prevention and/ or therapy of CVDs. One may predict that herbal remedies will receive even more attention in the coming years. However, some objective limitations should be considered based on the existing literature. Firstly, the CHM are widely examined in China. Accordingly, many articles published on the Chinese literature which may limit these work to be retrieved and public to the world. In addition, a location bias cannot be excluded since trials published in local periodicals are more likely to report significant outcomes than those published in worldwide mainstream medical periodicals. Secondly, many of the clinic trials were not well-designed and with poor methodological quality by lacking formal inclusion/ exclusion criteria, inadequate description of the randomization procedures, too short duration of therapy and follow-up to achieve conclusive outcomes, et al. Poorly designed and reported clinic roads usually exaggerate the therapy consequences which will misinform decision making in clinic. Thirdly, compounds contained in one herb, even in an extract of one herb are very complicated. Thus, it is a very tough work to clarify the mechanism of plant products/ herb for treating CVDs and interaction with other medicines( including western medicines ). Fourthly, many herbal medicine redress used today have not undergone careful scientific assessment and there still lack preclinical examine on the side effects, toxic effects and major drug-to-drug interactions in record. Even though, natural plants/ herbs are germs of medicine and should deserve more attention and application. Therefore, to develop new agents with effectiveness and safety from traditional Chinese medicine is a promising style for prevention and treatment of patients with CVDs. However, clinic examine criteria should be documented to standardize evaluation of plants/ herbs. In addition, international collaboration may be encouraged, promoted and financed from the governments in order to improve the overall research quality.

Author Contributions

CL drafted the run; YH revised the manuscript. Both CL and YH contributed substantially to the conception or design of the run, approved the final version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the run are appropriately investigated and resolved.

Funding

This work help support National Natural Science Foundation of China 8140264 6, Zhejiang Provincial Natural Science Fund for Distinguished Young Scholars of China LR1 7H260001, Hangzhou Science and Technology Plan Project of China 2014063 3B36 and the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education of China( to CL ).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abbreviations

ANP, atrial natriuretic peptide; BP, blood pressure; BKCa, channel Ca2+ -activated K+ channel; CHM, Chinese herbal medicine; CVDs, cardiovascular diseases; ECM, extracellular matrix;( e) NOS,( endothelium) nitric oxide synthase; HDL-C, high-density lipoprotein cholesterol; HO, heme oxygenase; HUVEC, human umbilical vein endothelial cells; IL, interleukin; KATP, ATP-sensitive potassium; KRGE, Korean Red Ginseng extract; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; NO, nitric oxide; PPARI +-, peroxisome proliferator-activated receptor-alpha; ROS, reactive oxygen species; Sal, salvianolic acid; SHR, spontaneous hypertension rats; SOD, superoxide dismutase; TC, total cholesterol; TG, triglyceride; VSMCs, vascular smooth muscle cells.

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Keywords: Chinese herbal medicine, hypertension, atherosclerosis, dyslipidemia, heart disease, cardiovascular diseases

Citation: Liu C and Huang Y( 2016) Chinese Herbal Medicine on Cardiovascular disease and the Mechanisms of Action. Front. Pharmacol. 7:469. doi: 10.3389/ fphar. 2016.00469

Received: 19 September 2016; Accepted: 18 November 2016;
Published: 01 December 2016.

Copyright A( c) 2016 Liu and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License( CC BY ). The employ, distribution or reproduction in other forums is permitted, the original writer( s) or licensor are credited and that the original publishing in this journal is cited, in accordance with accepted academic practice. No employ, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Cuiqing Liu, liucuiqing @zcmu. edu.cn Yu Huang, yu-huang @cuhk. edu.hk

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