心血管疾病病與達瑪烷人蔘皂苷
人類目前常見的疾病中,絕大部份與幹細胞的功能下降有關係。例如高血壓和動脈硬化,這些疾病的發生多與動脈的內皮細胞衰老或者損傷後得不到及時修復有關。而動脈內皮細胞的修復在很大程度上是由血液中的內皮祖細胞來承擔的。然而,隨著年齡的衰老,血液中的內皮祖細胞也逐漸喪失了活力,損傷或衰老的內皮細胞得不到修復,從而引發高血壓和動脈硬化,在此基礎上,造成心血管疾病(心肌梗塞,中風....等)的發生。
人體的老化由血管開始, 如果把血管比喻成一條河流,在正常情況下,河道應該是暢行無阻的,但若血液中所含膽固醇愈來愈高時,血液就會開始變濃稠,這些無法消化及排除的膽固醇便在血管中慢慢累積,而血管河道也隨之變窄,因而產生動脈粥狀硬化、血栓及中風的可怕結果。
家族成員中若有心血管疾病的相關病史,那罹患心血管疾病的機率就會比一般人高。肥胖是引發心血管疾病的危險因子之一,因肥胖者的血脂肪及血膽固醇通常偏高,易引起高血壓、冠狀動脈硬化及心臟病等疾病的發生率。 具有高血糖(空腹血糖值≧110mg/dL)、高血脂(三酸甘油脂≧150mg/dL)及高血壓(收縮壓≧130mmHg,舒張壓≧85mmHg)的三高族是心血管疾病發生的高危險群,此外,糖尿病、痛風及腎臟病等也會提高心血管疾病的風險。長期應酬熬夜、喝酒、抽煙、缺乏運動及飲食大魚大肉者也是使心血管疾病大幅提高的原因。
如果你屬於以上危險族群 你就必須及早開始保養你的心血管系統
達瑪烷人蔘皂苷對心血管系統的作用:
達瑪烷人參皂苷可有效活化幹細胞能, 預防與改善心血管相關疾病。高血壓和動脈粥樣硬化,這些疾病的發生多與動脈的內皮細胞衰老或者損傷後得不到及時修復有關。而動脈內皮細胞的修復在很大程度上是由血液中的內皮祖細胞來承擔的。隨著年齡的衰老,血液中的內皮祖細胞也逐漸喪失了活力,因而損傷或衰老的內皮細胞得不到修復,從而發生高血壓和動脈粥樣硬化,再次基礎上,進而發生冠心病(心肌梗塞等)和中風等。
1. 增加心肌供血量,減少心肌梗死面積 達瑪烷皂苷和苷元可明顯增強麻醉犬心肌血流量,降低冠狀動脈阻力,減少心肌耗氧量及降低心肌耗氧指數;同時能明顯降低麻醉犬動脈血壓、左心室壓力及其最大上升速率。達瑪烷皂苷及其代謝產物同時也能夠降低左心室舒張末壓力的增加,改善心臟射血分數和舒張功能。可見,達瑪烷皂苷和苷元抗心肌缺血和缺氧作用是通過多種途徑實現的。通過顯著改善心肌的供血能力和提高心肌的耐缺氧能力,達瑪烷皂苷和苷元能減小心肌梗死的面積。在動物實驗中,通過結紮冠狀動脈前降支造成缺血後,心臟表面心電描記顯示,事先服用達瑪烷皂苷的實驗狗的缺血面積和程度都比沒有服用達瑪烷皂苷的對照組要有明顯減少;同時硝基四氯唑藍染色表明,心肌梗死的面積也顯著減少;在超聲多普勒指標上,達瑪烷皂苷降低了冠狀動脈阻力,明顯地增加了心肌的血液供應。達瑪烷皂苷和苷元還能明顯減少異丙腎上腺素心肌損傷大鼠心肌壞死程度,反映心肌梗死的酶學指標(例如CK 和LDH)也得到了明顯的降低。達瑪烷皂苷還具有抗心肌缺氧的作用,如Rg2 靜脈注射明確地改善了心肌缺血引起的心電圖表現,縮小了心肌梗死的面積,也同時降低了心肌酶的血液水準。
2. 減少心肌缺血後再灌注的損傷 心肌梗死後血管再通並不一定伴隨心肌功能的恢復,反而會造成缺血再灌注損傷,進一步加重心肌的損傷程度,造成心肌頓抑。在臨床上,很多藥物,例如鈣離子拮抗劑、血管緊張素轉換酶抑制劑或血管緊張素受體拮抗劑、自由基清除劑等,都被用來對抗心肌缺血再灌注損傷,但效果都差強人意。達瑪烷皂苷和苷元的抗心肌缺血再灌注損傷作用優異,在接受心臟手術的病人中,達瑪烷皂苷能夠明顯改善心臟的收縮功能,減輕心肌細胞的損傷,有望成為新一代抗再灌注損傷的藥物。達瑪烷皂苷和苷元的抗心肌缺血再灌注損傷作用是通過以下作用來達到的:1)保護線粒體;2)降低鈣超載;3)抗氧化,清除自由基;4)抑制心肌細胞凋亡。
3. 抗心律失常的作用 對多種達瑪烷皂苷和苷元抗大鼠心律失常活性研究表明:當苷元不同、連接醣數目相同時,其活性強度順序為:原人參三醇型>齊墩果酸型>原人參二醇型;當苷元相同時,人參三醣苷>人參二醣型>人參單醣苷。基礎的研究已經證實,達瑪烷皂苷和苷元能通過穩定心肌細胞膜的電位來有效地減少心律失常的發生。在心肌缺血再灌注的模型中,沒有經達瑪烷皂苷處理的實驗組中,有44%的大鼠死於心室顫動,但是,經達瑪烷皂苷預處理的大鼠,無一例發生心室顫動和死亡,其他的再灌注心律失常也明顯減少。在黃嘌呤氧化酶損傷的大鼠心肌細胞中,人參三醇和二醇達瑪烷苷元能夠恢復細胞的動作電位。另外,達瑪烷皂苷能保護竇房結的功能。當給予兔子短期或長期的總皂苷注射(50mg/kg.d)後,竇房結的自發週期長度,最大竇房結恢復時間,糾正後竇房結恢復時間(spontaneous cycle length (SCL), maximal sinus node recovery time (SNRTmax), corrected sinus noderecovery time (CSNRT)較對照組都明顯縮短。達瑪烷皂苷還能縮短心肌細胞動作電位的時程和自發收縮,減少異位搏動的產生。進一步的電生理研究顯示,皂苷的這種作用可能與拮抗鈣離子通道和增強緩慢啟動延遲整流鉀電流(delayed rectifier K+ current)有關。
4. 改善血管內皮功能,調節血壓 內皮在機體的凝血,抗血小板,和血壓調控中發揮了重要的作用,內皮的功能失常與動脈硬化和心血管疾病有密切的聯繫。最新的研究表明,達瑪烷皂苷和苷元能有效的保護內皮功能,對動脈硬化及其後續的併發症起到預防作用。冠心病的危險因子同型半胱氨酸能夠損傷內皮,造成內皮的舒張功能紊亂。經過達瑪烷皂苷處理的冠狀動脈血管環能夠有效地對抗同型半胱氨酸的作用,血管舒張和內皮細胞功能恢復到正常水準。這種內皮保護的作用同樣出現在兔子的模型中,達瑪烷皂苷能夠恢復高膽固醇血症引起的內皮功能紊亂。達瑪烷皂苷的這種作用被認為是通過增加一氧化氮合酶表達,進而增加血管局部一氧化氮產生來發揮的。在自發性高血壓大鼠中,達瑪烷苷元能夠有效地抑制收縮壓的升高。
5. 調節血脂,對抗動脈粥樣硬化 在動物試驗中,達瑪烷皂苷有效地抑制了膽固醇合成的限速酶HMG-CoA 還原酶的活性,同時膽固醇7α 羥化酶也受到了抑制;從而降低血液中的總膽固醇(17%~33%)、低密度脂蛋白水準(19%~47%);同時甘油三酯的水準也減低。達瑪烷皂苷配合有氧鍛煉能進一步降低血液中膽固醇和甘油三酯的水準。達瑪烷皂苷也能影響高密度脂蛋白的表達,增加脂蛋白AI(高密度脂蛋白的主要成分)生成,進而升高血液中的高密度脂蛋白的水平。
人類目前常見的疾病中,絕大部份與幹細胞的功能下降有關係。例如高血壓和動脈硬化,這些疾病的發生多與動脈的內皮細胞衰老或者損傷後得不到及時修復有關。而動脈內皮細胞的修復在很大程度上是由血液中的內皮祖細胞來承擔的。然而,隨著年齡的衰老,血液中的內皮祖細胞也逐漸喪失了活力,損傷或衰老的內皮細胞得不到修復,從而引發高血壓和動脈硬化,在此基礎上,造成心血管疾病(心肌梗塞,中風....等)的發生。
人體的老化由血管開始, 如果把血管比喻成一條河流,在正常情況下,河道應該是暢行無阻的,但若血液中所含膽固醇愈來愈高時,血液就會開始變濃稠,這些無法消化及排除的膽固醇便在血管中慢慢累積,而血管河道也隨之變窄,因而產生動脈粥狀硬化、血栓及中風的可怕結果。
家族成員中若有心血管疾病的相關病史,那罹患心血管疾病的機率就會比一般人高。肥胖是引發心血管疾病的危險因子之一,因肥胖者的血脂肪及血膽固醇通常偏高,易引起高血壓、冠狀動脈硬化及心臟病等疾病的發生率。 具有高血糖(空腹血糖值≧110mg/dL)、高血脂(三酸甘油脂≧150mg/dL)及高血壓(收縮壓≧130mmHg,舒張壓≧85mmHg)的三高族是心血管疾病發生的高危險群,此外,糖尿病、痛風及腎臟病等也會提高心血管疾病的風險。長期應酬熬夜、喝酒、抽煙、缺乏運動及飲食大魚大肉者也是使心血管疾病大幅提高的原因。
如果你屬於以上危險族群 你就必須及早開始保養你的心血管系統
達瑪烷人蔘皂苷對心血管系統的作用:
達瑪烷人參皂苷可有效活化幹細胞能, 預防與改善心血管相關疾病。高血壓和動脈粥樣硬化,這些疾病的發生多與動脈的內皮細胞衰老或者損傷後得不到及時修復有關。而動脈內皮細胞的修復在很大程度上是由血液中的內皮祖細胞來承擔的。隨著年齡的衰老,血液中的內皮祖細胞也逐漸喪失了活力,因而損傷或衰老的內皮細胞得不到修復,從而發生高血壓和動脈粥樣硬化,再次基礎上,進而發生冠心病(心肌梗塞等)和中風等。
1. 增加心肌供血量,減少心肌梗死面積 達瑪烷皂苷和苷元可明顯增強麻醉犬心肌血流量,降低冠狀動脈阻力,減少心肌耗氧量及降低心肌耗氧指數;同時能明顯降低麻醉犬動脈血壓、左心室壓力及其最大上升速率。達瑪烷皂苷及其代謝產物同時也能夠降低左心室舒張末壓力的增加,改善心臟射血分數和舒張功能。可見,達瑪烷皂苷和苷元抗心肌缺血和缺氧作用是通過多種途徑實現的。通過顯著改善心肌的供血能力和提高心肌的耐缺氧能力,達瑪烷皂苷和苷元能減小心肌梗死的面積。在動物實驗中,通過結紮冠狀動脈前降支造成缺血後,心臟表面心電描記顯示,事先服用達瑪烷皂苷的實驗狗的缺血面積和程度都比沒有服用達瑪烷皂苷的對照組要有明顯減少;同時硝基四氯唑藍染色表明,心肌梗死的面積也顯著減少;在超聲多普勒指標上,達瑪烷皂苷降低了冠狀動脈阻力,明顯地增加了心肌的血液供應。達瑪烷皂苷和苷元還能明顯減少異丙腎上腺素心肌損傷大鼠心肌壞死程度,反映心肌梗死的酶學指標(例如CK 和LDH)也得到了明顯的降低。達瑪烷皂苷還具有抗心肌缺氧的作用,如Rg2 靜脈注射明確地改善了心肌缺血引起的心電圖表現,縮小了心肌梗死的面積,也同時降低了心肌酶的血液水準。
2. 減少心肌缺血後再灌注的損傷 心肌梗死後血管再通並不一定伴隨心肌功能的恢復,反而會造成缺血再灌注損傷,進一步加重心肌的損傷程度,造成心肌頓抑。在臨床上,很多藥物,例如鈣離子拮抗劑、血管緊張素轉換酶抑制劑或血管緊張素受體拮抗劑、自由基清除劑等,都被用來對抗心肌缺血再灌注損傷,但效果都差強人意。達瑪烷皂苷和苷元的抗心肌缺血再灌注損傷作用優異,在接受心臟手術的病人中,達瑪烷皂苷能夠明顯改善心臟的收縮功能,減輕心肌細胞的損傷,有望成為新一代抗再灌注損傷的藥物。達瑪烷皂苷和苷元的抗心肌缺血再灌注損傷作用是通過以下作用來達到的:1)保護線粒體;2)降低鈣超載;3)抗氧化,清除自由基;4)抑制心肌細胞凋亡。
3. 抗心律失常的作用 對多種達瑪烷皂苷和苷元抗大鼠心律失常活性研究表明:當苷元不同、連接醣數目相同時,其活性強度順序為:原人參三醇型>齊墩果酸型>原人參二醇型;當苷元相同時,人參三醣苷>人參二醣型>人參單醣苷。基礎的研究已經證實,達瑪烷皂苷和苷元能通過穩定心肌細胞膜的電位來有效地減少心律失常的發生。在心肌缺血再灌注的模型中,沒有經達瑪烷皂苷處理的實驗組中,有44%的大鼠死於心室顫動,但是,經達瑪烷皂苷預處理的大鼠,無一例發生心室顫動和死亡,其他的再灌注心律失常也明顯減少。在黃嘌呤氧化酶損傷的大鼠心肌細胞中,人參三醇和二醇達瑪烷苷元能夠恢復細胞的動作電位。另外,達瑪烷皂苷能保護竇房結的功能。當給予兔子短期或長期的總皂苷注射(50mg/kg.d)後,竇房結的自發週期長度,最大竇房結恢復時間,糾正後竇房結恢復時間(spontaneous cycle length (SCL), maximal sinus node recovery time (SNRTmax), corrected sinus noderecovery time (CSNRT)較對照組都明顯縮短。達瑪烷皂苷還能縮短心肌細胞動作電位的時程和自發收縮,減少異位搏動的產生。進一步的電生理研究顯示,皂苷的這種作用可能與拮抗鈣離子通道和增強緩慢啟動延遲整流鉀電流(delayed rectifier K+ current)有關。
4. 改善血管內皮功能,調節血壓 內皮在機體的凝血,抗血小板,和血壓調控中發揮了重要的作用,內皮的功能失常與動脈硬化和心血管疾病有密切的聯繫。最新的研究表明,達瑪烷皂苷和苷元能有效的保護內皮功能,對動脈硬化及其後續的併發症起到預防作用。冠心病的危險因子同型半胱氨酸能夠損傷內皮,造成內皮的舒張功能紊亂。經過達瑪烷皂苷處理的冠狀動脈血管環能夠有效地對抗同型半胱氨酸的作用,血管舒張和內皮細胞功能恢復到正常水準。這種內皮保護的作用同樣出現在兔子的模型中,達瑪烷皂苷能夠恢復高膽固醇血症引起的內皮功能紊亂。達瑪烷皂苷的這種作用被認為是通過增加一氧化氮合酶表達,進而增加血管局部一氧化氮產生來發揮的。在自發性高血壓大鼠中,達瑪烷苷元能夠有效地抑制收縮壓的升高。
5. 調節血脂,對抗動脈粥樣硬化 在動物試驗中,達瑪烷皂苷有效地抑制了膽固醇合成的限速酶HMG-CoA 還原酶的活性,同時膽固醇7α 羥化酶也受到了抑制;從而降低血液中的總膽固醇(17%~33%)、低密度脂蛋白水準(19%~47%);同時甘油三酯的水準也減低。達瑪烷皂苷配合有氧鍛煉能進一步降低血液中膽固醇和甘油三酯的水準。達瑪烷皂苷也能影響高密度脂蛋白的表達,增加脂蛋白AI(高密度脂蛋白的主要成分)生成,進而升高血液中的高密度脂蛋白的水平。
J Ginseng Res. 2012 January; 36(1): 16–26.
doi: 10.5142/jgr.2012.36.1.16
PMCID: PMC3659571
Cardiovascular Diseases and Panax ginseng: A Review on Molecular Mechanisms and Medical Applications
Jong-Hoon Kim*
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Abstract
Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications. Ginseng may also be potentially valuable in treating cardiovascular diseases. Research concerning cardiovascular disease is focusing on purified individual ginsenoside constituents of ginseng to reveal specific mechanisms instead of using whole ginseng extracts. The most commonly studied ginsenosides are Rb1, Rg1, Rg3, Rh1, Re, and Rd. The molecular mechanisms and medical applications of ginsenosides in the treatment of cardiovascular disease have attracted much attention and been the subject of numerous publications. Here, we review the current literature on the myriad pharmacological functions and the potential benefits of ginseng in this area. In vitroinvestigations using cell cultures and in vivo animal models have indicated ginseng’s potential cardiovascular benefits through diverse mechanisms that include antioxidation, modifying vasomotor function, reducing platelet adhesion, influencing ion channels, altering autonomic neurotransmitters release, and improving lipid profiles. Some 40 ginsenosides have been identified. Each may have different effects in pharmacology and mechanisms due to their different chemical structures. This review also summarizes results of relevant clinical trials regarding the cardiovascular effects of ginseng, particularly in the management of hypertension and improving cardiovascular function.
Keywords: Panax ginseng, Cardiovascular disease(CVD), Myocardial ischemia, Vasomotor tone, Lipid profile, Antioxidants
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INTRODUCTIONCardiovascular disease (CVD) is an important problem among the 400 million indigenous populations around the world, and have been included in the World Health Organization ‘2008-2013 Action plan for noncommunicable diseases’[1]. CVD, which encompasses a spectrum of diseases including coronary artery disease, peripheral vascular disease, congestive heart failure, dyslipidemias, and hypertension, affects millions of Americans and is perennial among the leading causes of morbidity and mortality [2]. These diseases are common and occur in infants, children, and adults of both genders, affecting people of all races and ethnicities. The lifetime risk for a 40-year-old developing coronary heart disease is roughly 50% for men and 32% for women [3]. Over the past 50 years, it has become clear that the cascade of thrombotic events following atherosclerotic plaque rupture causes occlusion of the coronary artery, which interrupts the supply of blood and oxygen to the myocardium, resulting in infarction. Myocardial necrosis following infarction is followed by heart failure, myocardial rupture, or arrhythmia [4]. Despite enormous strides in the last five decades, myocardial infarction, stroke, and sudden death remain the principal causes of morbidity and mortality in industrialized nations. Among the most important of these CVD are dyslipidemia, hypertension, age, smoking status, insulin resistance, diabetes mellitus, and family history for premature coronary artery disease [5]. Also, atherosclerosis and acute coronary syndrome are now recognized as manifestations of vascular inflammation [6,7]. Risk factors for CVD promote endothelial dysfunction. Dysfunctional endothelial cells express adhesion molecules, which promote the binding and influx of inflammatory white blood cells (T-cells and mast cells) into the subendothelial space [8]. White blood cells produce interleukins, cytokines, and reactive oxygen species, which create an inflammatory focus within the arterial wall. Atherogenic lipoproteins such as low-density lipoprotein access the subendothelial space where they become trapped within the network of intercellular matrix proteins and undergo enzymatic oxidative modification, aggregation, and, ultimately, uptake by macrophages. This process leads to the development of foam cells [9,10]. Heart disease is the leading cause of death among all ages, and cardiac infarction remains the major cause of death (Fig. 1) [11,12]. This is the foremost reason why CVD is a major area of longevity research.
Fig. 1.
Pathway relating cardiovascular disease (CVD) mortality. The established CVD risk factors lie in the middle of a chain of events that leads to cardiac death.
Ginseng has been used for over 2,000 years, in the belief that it is a panacea and promotes longevity. Panax ginseng is a traditional medicinal plant that has been used therapeutically for millennia in the Orient. Particularly in Korea, China, and Japan, it is the most valuable of all medicinal herbs. The namePanax means ‘all healing,’ which describes the traditional belief that ginseng has properties to heal all aspects of the body. The most common ginsengs are Korean red ginseng (P. ginseng Meyer), Chinese ginseng (P. notoginseng) and American ginseng (P. quinquefolium L.). Despite this rich history, the basis of the plant’s medicinal prowess was unknown until the isolation of the active constituents (ginsenosides) beginning in 1963 [13,14]. Much effort has since been focused on evaluating the function and elucidating the molecular mechanism of each ginsenoside. This is reflected in the exploding number of PubMed cited publications on ginseng and ginsenosides since 1975. Research now focuses on the study of purified individual ginsenosides instead of using whole ginseng root [15-20]. Each ginsenoside may have different pharmacologic effect(s) and mechanism(s) reflective of their different structures. Approximately 40 ginsenosides have been identified as of 2012, and the various methods of separation and analysis are well-reviewed [21]. The most commonly studied ginsenosides are Rb1, Rg1, Rg3, Re, and Rd. A detailed review about the anti-amnestic and anti-aging effects and action mechanisms of Rb1 and Rg1 has been published [20].
Moreover, ginseng and its ginsenoside constituents are thought to possess vasorelaxation, anti-oxidation, anti-inflammation, and anti-cancer activities. Ginsenosides also showed the effects on the central nervous system and the peripheral nervous system [22]. Furthermore, ginseng’s long-lasting prowess has been demonstrated as well as its enhanced benefit in a disease state than a healthy state [23-25]. Additionally, a previous study reported the molecular mechanisms and cardiovascular clinical applications of ginseng [19].
Koreans have traditionally used P. ginseng roots and root extracts to revitalize the body and mind, increase physical strength, prevent aging, and increase vigor. A new pharmacological concept of the tonic effect of ginseng has arisen[26], resulting in interest and attention by explaining the basic pharmacology of ginseng with adaptogen effects. Ginseng use is common in individuals who have cardiovascular risk factors, such as hypertension, hypercholesterolemia, and oxidative damage. Yet, its’ cardiovascular safety and efficacy are unclear. This review summarizes the current knowledge regarding the efficacy of ginseng on the major cardiovascular risk factors of blood pressure, cardiac ischemia, vasomotor activity, lipid profile, and oxidative stress.
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EFFICACY OF REGULATING INTRACELLULAR ION CHANNELSIn the heart, calcium ion (Ca2+) is crucial for the regulation of contraction and intracellular signaling, which are vital to heart function. Ca2+-activated signaling pathways must function against a background of large, rapid, and tightly regulated changes in intracellular free Ca2+ concentrations during each contraction and relaxation cycle (Fig. 2).
Fig. 2.
Role of sodium- and calcium-overload in the pathogenesis of hypercontracture after cardiac ischemia/reperfusion.
Ginsenoside Rb1 inhibits cardiac hypertrophy in a rat model [27]. Ginsenoside Rd reverses basilar hypertrophic remodeling in stroke-prone renovascular hypertensive rats as a new voltage-independent Ca2+ entry blocker [28]. Also, the effect of sugar position in ginsenosides on inhibitory potency of Na+/K+-ATPase activity has been described [29]. Another study reported that mutations in the Leu427, Asn428, and Leu431 residues attenuate ginsenoside-mediated L-type Ca2+ channel current inhibition [30]. The data indicate that ginsenosides inhibit Ca2+ entry, and so may ameliorate cardiac function.
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EFFICACY OF ADJUSTING BLOOD PRESSUREGinseng use was once rumored to increase blood pressure to unhealthy levels. While ginseng can elevate blood pressure, this generally occurs with low blood pressure, which helps restore blood pressure to normal; ginseng also lowers high blood pressure [31]. Biochemical and pharmacological activities of ginseng related to blood pressure control are being clarified with continued research. The vasodilation action of P. ginseng improves blood circulation[32]. Korean red ginseng has an antihypertensive effect, which appears to be related to lower rather than higher doses of ginsenosides [33]. In addition, the blood pressure lowering activity of P. ginseng is due to promotion of vascular endothelial cell-derived nitric oxide (NO) secretion [32,34]. Furthermore, a mixed aqueous extract of salvia miltiorrhiza and P. notoginseng demonstrated anti-hypertensive effects by inhibition of arterial myogenic responses [35]. The collective observations indicate that ginseng normalizes blood pressure and improves blood circulation.
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EFFICACY OF IMPROVING MYOCARDIAL PROTECTIONGinseng has been used for treatment of heart failure and to protect tissues from damage when an organism is under stress [36]. These attributes come with the added advantage of an absence of harmful side effects. Saponins fromP. notoginseng protect against doxorubicin-induced cardiotoxicity in mice[37]. Total ginsenosides inhibit right ventricular hypertrophy in rats [38] and nitric oxide functions in ginsenoside Rg1-induced protection against left ventricular hypertrophy in rats [39]. Ginsenoside Re suppresses electromechanical alternans in cat and human cardiomyocytes [40] and ginsenoside Rb1 preconditioning protects against myocardial infarction after regional ischemia and reperfusion [41]. Left ventricular hypertrophy in rats is also inhibited by ginsenoside Rg1 [42]. Another study suggested that P. ginseng suppresses apoptosis by regulation of Bcl-2 and caspase-3 during hypoxia/reoxygenation in neonatal rat cardiomyocytes [43]. The effects of wild ginseng and astragali radix pharmacopuncture have been compared on the autonomic nervous system and heart rate variability [44]. In addition, ginsenoside Rg1 protects rat cardiomyocyte from hypoxia/reoxygenation oxidative injury via antioxidant and intracellular calcium homeostasis [45]. The protective effects of ginseng total saponin, panaxadiol, and panaxatriol on ischemia/reperfusion injury have been documented in isolated rat heart [46]. The protective role of ginsenoside Rb1 against myocardial ischemia/reperfusion injury in streptozotocin-induced diabetic rats has been reported [47], as has the role of ginseng in reducing adverse post-myocardial remodeling [48]. The results of another study supported the suggestion that ginseng inhibits cardiomyocyte hypertrophy and heart failure via Nhe-1 inhibition and attenuation of calcineurin activation [49]. Furthermore, compound K, a metabolite of ginsenosides, bestows nitric oxide-mediated cardiac protection via the Akt/phosphoinositol-3-kinase (PI3K) pathway [50]. Ginseng also protects from cardiac injury by acute myocardial ischemia-reperfusion in rodents through Gr/ Er-activated risk pathway in an endothelial nitric oxide synthase (eNOS)-dependent mechanism [51]. The collective data conclusively indicate that ginseng protects from myocardial damage.
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EFFICACY OF REGULATING VASCULAR ENDOTHELIAL CELLSIndividuals with peripheral arterial disease typically have atherosclerotic disease affecting several vascular beds, including coronary, cerebral, and renal beds [52]. This may account for both the increased cardiac morbidity and mortality [53]. Scientifically proven pharmacological effects of ginseng on vascular endothelial cells are as follows. Ginsenoside Rb1 has effects on human umbilical vein endothelial cells in vitro [54]. Water extract of Korean red ginseng exhibits angiogenesis by activating the PI3K/Akt-dependent extracellular signal-regulated kinase 1/2 and eNOS pathways in human umbilical vein endothelial cells [55]. Ginsenosides also exhibit angiomodulatory and neurological effects [56]. Moreover, ginsensoside Re activates potassium channels of vascular smooth muscle cells through PI3k/Akt and NO pathways [57]. In addition, ginsenoside-Re has nongenomic effects of in endothelial cells via the glucocorticoid receptor [58]. Ginsenoside Rb1 may attenuate capillary morphogenesis by the action of oestrogen receptor beta agonist [59] and induces the signaling pathway of NO production in human aortic endothelial cells [60]. Ginsenoside Rg1 and Re isolated from P. ginseng are stable angiogenic agents [61]. Extracts from P. notoginseng and P. ginseng fruit enhance vascular endothelial cell proliferation and migration in vitro [62]. Moreover, experiments using fluorescent transgenic mice established the angiogenic effect of ginsenoside Rg1 from P. ginseng [63]. The role of this ginsenoside Rg1 in the induction of angiogenesis was also established in another study [64]. The angiogenic effect of saponin extract from P. notoginseng on human umbilical vein endothelial cells in vitro and zebrafish in vivo has been described [65]. The results of another study suggested that P. notoginseng reduces atherosclerotic lesions in ApoE-deficient mice and inhibits tumor necrosis factor-alpha-induced endothelial adhesion molecule expression and monocyte adhesion [66]. Ginsenoside Rg3increases NO production via increases in phosphorylation and expression of eNOS [67]. Compound K inhibits basic fibroblast growth factor-induced angiogenesis through regulation of p38 mitogen-activated protein kinase and Akt in human umbilical vein endothelial cells [68]. Ginsenoside Rg1 induces angiogenesis via non-genomic crosstalk of glucocorticoid receptor and fibroblast growth factor receptor 1 [69] and mediates the microenvironment-dependent endothelial differentiation of human mesenchymal stem cells in vitro [70]. Furthermore, ginsenoside Rb1 protects against endothelial cell damage and stimulates ghrelin expression induced by hyperhomocysteine [71]. These collective observations suggest that ginseng saponin protects vascular endothelial cells via cellular signaling pathway.
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EFFICACY OF REGULATING VASOMOTOR FUNCTIONSThe cardiovascular effects of ginseng and individual ginsenosides have been amply reviewed. Many reports describe transient vasodilator actions, in some cases followed by vasoconstriction and an increase in blood pressure. The endothelium contributes to the control of vascular smooth muscle tone by production and release of NO, which accounts for the biological activity of the endothelium- derived relaxing factor [72-74]. Ginsenosides have been shown to stimulate NO production in several systems. One study examined purified ginsenoside Rb1- induced NO production in human aortic endothelial cells[60]. Another study reported that this ginsenoside increased the phosphorylation of glucocorticoid receptor, PI3K, Akt/protein kinase B, and eNOS, leading to increased NO production in human umbilical vein endothelial cells [75]. Other studies investigated the relaxation mechanism of ginsenoside Rg3 using isolated canine corpus cavernosum [76] and demonstrated the effects of Korean red ginseng and its isolated ginsenosides and polysaccharides on arterial stiffness in healthy individuals [77]. Studies with ginsenoside Rg3 reported induced vascular smooth muscle dysfunction and remodeling [78] and the inhibition of angiotensin II-induced vascular smooth muscle cell proliferation [79]. The effects of total saponins of P. notoginseng on aortic intimal hyperplasia and the expression of cell cycle protein and extracellular matrix in rats has been reported [80]. Finally, the benefit of Korean red ginseng on arterial stiffness in subjects with hypertension was reported [81]. Together, these results indicate that ginseng and ginsenosides ameliorate vasomotor function.
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EFFICACY OF IMPROVING BLOOD CIRCULATIONReports have documented ginseng’s inhibitory effects on platelet aggregation[82] and endotoxin-induced disseminated intravascular coagulation [83], which has led to the use of ginseng, particularly Korean red ginseng, as an anti-thrombotic and fibrinolytic agent [84]. The role of ginsenoside Rg3 in the inhibition of platelet aggregation has been described [85]. The role of ginsenosides in protecting human erythrocytes against hemin-induced hemolysis has been described [86]. Screening of anti-platelet aggregation agents from P. notoginseng can be done using human platelet extraction [87].P. notoginseng saponins improve the post-treatment effects on lipopolysaccharide-induced microcirculatory disturbance in rat mesentery[88]. Anti-platelet and anti-coagulant effects of P. notoginseng were described in a comparison of raw and steamed P. notoginseng with P. ginseng and P. quinquefolium [89]. The platelet anti-aggregating activity of ginsenosides isolated from ginseng has been reported [90,91]. Another study documented the interaction between warfarin and Korean red ginseng in patients with cardiac valve replacement [92]. Total ginsenosides increase coronary perfusion flow in isolated rat hearts by activating PI3K/Akt-eNOS signaling [93]. Red ginseng extract improves coronary flow reserve and increases absolute numbers of various circulating angiogenic cells in patients with acute myocardial infarction [94]. Overall, these results suggest that ginseng may improve blood circulation by inhibiting platelet aggregation and coagulation activity.
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EFFICACY OF ADJUSTING BLOOD LIPID PROFILEMetabolic syndrome – defined as a cluster of three of insulin resistance and glucose intolerance, abdominal obesity, hypertension, low high density lipoprotein cholesterol, and hypertriglyceridemia – has become a global epidemic. The prevalence of metabolic syndrome in adults has been increasing rapidly in the past decades in most western countries, and the situation is even worse in people over 60-years-of-age [95]. Given the fact that people who have metabolic syndrome are susceptible to atherosclerotic CDV [96], effective and feasible therapeutic strategies are urgently needed for the treatment of complications of metabolic syndrome. In recent years, more attention has been paid to bioactive components from P. ginseng. Particularly, it was reported that P. ginseng saponin reduces weight gain in mice [97]. Bifidus fermentation was shown to increase the hypolipidemic and hypoglycemic effects of red ginseng [98]. Korean red ginseng attenuates hypercholesterolemia-enhanced platelet aggregation by suppressing diacylglycerol liberation in rabbits fed a diet high in cholesterol [99]. P. notoginseng saponins attenuate atherosclerosis by regulating the lipid profile and have an anti-inflammatory action in rats[100] and atherosclerosis is inhibited by total P. notoginsenosides in apolipoprotein E-knockout mice [101]. Also, cholesterol ester can be decreased by P. notoginseng saponins by the up-regulation of the ATP-binding cassette transporter A1 in foam cells [102]. The anti-hyperlipidemic effects of acidic polysaccharide from Korean red ginseng were reported [103]. P. notoginsengsaponins attenuate atherogenesis in rabbits [104] and radix notoginseng has hypolipidemic and anti-oxidant activities in rats fed a high fat diet [105]. Ginsenoside-Rd prevents atherosclerosis in ApoE-knockout mice [106]. Overall, these results suggest that P. ginseng improves the lipid profile.
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OXIDATION AND GINSENGThe production of reactive oxygen species (ROS) from various cellular metabolic processes caused by the restoration of coronary flow after cardiac ischemia is thought to contribute to myocardial damage [107-109]. ROS cause non-specific damage to lipids, proteins and DNA, leading to an alteration or loss of the cellular function. The abrupt rise in ROS as a result of the reoxygenation of ischemic or hypoxic cardiac muscle has been associated with a partially irreversible inhibition of mitochondrial respiration [110]. Alterations in generation and/or use of energy are thought to be important contributing factors to the observed dysfunction caused by ischemia reperfusion injury [111]. It is recognized that a free radical that is produced in excess of what is reasonably sufficient in the body may induce CVD. Therefore, extensive studies have been conducted on the cardioprotective effects of ginseng against free radical damage.
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EFFICACY OF ANTI-OXIDANT ACTIVITYThe scientifically-proven pharmacological effects of ginseng against oxidative damage are as follows. Ginseng and ginsenosides have an anti-oxidant effect that is manifest as an inhibited increase in harmful free radical formation and lipid peroxidation [112-116]. Ginsenosides Rg2 and Rh1 protect from oxidation-induced impairment of erythrocyte membrane properties [117]. P. ginsengpolysaccharide is effective in the regulation of energy metabolism and protection of mitochondria [118]. Studies with American ginseng reported the mediation of anti- -oxidant actions via Nrf2 in cardiomyocytes [119] and ginseng-related increased activity of the antioxidant enzymes, superoxide dismutase and glutathione peroxidase in rats [120]. Another in vivo study reported that ginsenosides protected against myocardial reperfusion damage with a concomitant increase in 6-keto-prostaglandin F1a and a decrease in lipid peroxidation, and also protected rabbit pulmonary and aortic endothelium against electrolysis- induced free radical damage [121]. Ginsenosides also protected rabbit pulmonary endothelium from injury induced by a variant of ROS [15]. Also, it was reported that ginseng prevented manifestations of ROS injury by promoting the release of NO. Endothelial dysfunction induced by homocysteine and human immunodeficiency virus protease inhibitors can be effectively blocked by Rb1 and other ginsenosides[122,123], confirming the role of ginsenoside Rb1 and other ginsenosides in blocking ROS production. In addition, ginsenoside Re possesses anti-oxidant effects in cardiomyocytes [124]. Ginsenosides exert their anti-oxidant ability by increasing internal antioxidant enzymes and acting as a freeradical scavenger [125-127]. Moreover, individual ginsenosides behave as an anti-oxidant if glucose is attached to the 20-position of the triterpene dammarane, such as Re, Rd, and R1, but as a pro-oxidant if there are no sugar moieties attached to the 20-position of the ginsenoside such as Rg3, Rh2, and Rg2 [128]. If a glucose is attached to the 6-position instead of 20-position sugar moieties, however, the ginsenoside still act as an anti-oxidant (e.g., Rh1) [128]. Overall, these results suggest that ginseng may inhibit oxidative damage due to prevention of ROS generation.
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CONCLUSIONGinseng is a traditional herbal medicine whose history stretches back millennia. The basis of ginseng’s prowess is its’ many active constituent ginsenosides. Ginseng has extensive pharmacological activities and specific mechanisms of action. Ginsenosides can inhibit ROS production, stimulate NO production, increase blood circulation, ameliorate vasomotor tone, and adjust lipid profile. Additionally, many studies indicate that ginsenosides have a multitude of activities in both physiological and/or pathologic conditions concerning with CVD. How these effects relate to the ginsenoside structures are still not yet fully understood. Future cardiovascular studies involving each ginsenoside should include the mechanisms of action in more detail, with emphasis on specificity, structure and function relationship, detailed pharmacokinetics and toxicity researches, and therapeutic studies in both animal and human models.
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