Ginsenoside Re: Pharmacological Effects on Cardiovascular System

REVIEW

Ginsenoside Re: Pharmacological Effects on Cardiovascular System Lu Peng,1,2 Shi Sun,3 Lai-Hua Xie,4 Sheila M. Wicks5 & Jing-Tian Xie2,6 1 Section of Cardiology, Internal Medicine, JiShuiTan Hospital, Beijing 100035, China 2 The Ben May Department for Cancer Research, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA 3 Institute of Botany, Jiangsu Province and Chinese Academy of Science, Nanjing 210014, China 4 Department of Cell Biology & Molecular Medicine, UMDNJ-New Jersey Medical School, 185 South Orange Ave. MSB C609, Newark, NJ 07103, USA 5 City Colleges of Chicago/Biological Sciences, 1901 W. VanBuren Street, Chicago, IL 60619 6 Shangqiu Medical College, Shangqiu, Henan Province, China

Keywords Cardiovascular system; Chemistry; Electrophysiology; Ginseng; Ginsenoside Re; Pharmacological effect. Correspondence Jing-Tian Xie, M.D., The Ben May Dept for Cancer Research, The University of Chicago, 929 E. 57th Street, Room 325, Chicago, IL 60637, USA. Tel.: (773) 702-6991; Fax: (773) 702-4476; E-mail: [email protected] and Lai-Hua Xie, Ph.D., Department of Cell Biology & Molecular Medicine, UMDNJ-New Jersey Medical School, 185 South Orange Ave. MSB C609, Newark, NJ 07103, USA. Tel.: (973) 972-2411; Fax: (973) 972-7489; E-mail: [email protected]

SUMMARY Ginsenosides are the bioactive constituents of ginseng, a key herb in traditional Chinese medicine. As a single component of ginseng, ginsenoside Re (G-Re) belongs to the panaxatriol group. Many reports demonstrated that G-Re possesses the multifaceted beneficial pharmacological effects on cardiovascular system. G-Re has negative effect on cardiac contractility and autorhythmicity. It causes alternations in cardiac electrophysiological properties, which may account for its antiarrhythmic effect. In addition, G-Re also exerts antiischemic effect and induces angiogenic regeneration. In this review, we first outline the chemistry and the pharmacological effects of G-Re on the cardiovascular system.

doi: 10.1111/j.1755-5922.2011.00271.x

Introduction Ginseng, known as the king of herbs, holds an important position in traditional Chinese medicine [1–3]. Botanically, ginseng plant is a slow-growing, shade-loving perennial herb of the Araliaceae family, cultivated in China, Japan, Korea, and Russia, as well as in the United States and Canada. Ginseng root has been used as an oriental folk medicine for several thousand years [2,4]. A large number of reports suggest that both American and Asian ginseng have diverse components and multifarious pharmacological functions [5–12]. The pharmacological properties of ginseng are mainly attributed to ginsenosides, the major and bioactive constituents [6,13]. In order to explore the pharmacological activities of ginseng in detail and underlying mechanism(s), a few researchers

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focus on using purified individual ginsenosides instead of using whole ginseng extracts [1]. Individual ginsenosides may have different pharmacological effects and mechanisms due to their different chemical structures. With the development of modern technology, more than 150 ginsenosides have been isolated and identified roots, leaves/stems, fruits, and/or flower heads of ginseng [14–17]. Ginsenoside Re (G-Re, C53 H90 O22 ) is a major ginsenoside and important ingredient in ginseng leaf, berry, and root [18,19]. Literatures have shown that G-Re exhibits multiple pharmacological activities via different mechanisms both in vivo and in vitro [13,20–27]. However, the pharmacological effect of G-Re on cardiovascular system and its possible metabolism have not yet been systematically outlined in literature. The purpose of this review is

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ginseng leaf-stem may be a valuable source for extracting of G-Re [42]. The content and composition of ginsenosides in ginseng are not exact and very dependent on the species, age, season of harvest, part of the plant, method of cultivation, and means of preservation [36]. In addition, multiple biological and environmental factors affect the quantity and quality of ginsenosides in ginseng [44]. Lim et al. reported that genotype and environmental effects on ginsenoside content among eight wild populations of American ginseng. The data indicated that the influence of genotype and environment on ginsenoside content was various to different types of ginsenosides [45]. A report also showed that a quantitative analysis of G-Re, GRb1, and G-Rg1 in American ginseng berry and flower samples, which were collected in various months throughout the year, and performed by enzyme-linked immunosorbent assay (ELISA). The American ginseng flower had the highest content of G-Re, GRb1, and G-Rg1 compared to berry. The lowest content of G-Re was found in berries harvested on September (6.95 μg/mg dry weight) [46]. To evaluate and analyses G-Re in American ginseng berry pulp extracts, a new eastern blotting technique has been established using anti-G-Re monoclonal antibody [47]. The results showed that there are different content of G-Re in disparate parts of ginseng. Figure 1 Chemical structures of protopanaxadiol, protopanaxatriol (A), and ginsenoside Re (B).

Pharmacological Effects of G-Re on the Cardiovascular System to introduce the chemistry, multifaceted pharmacological effects, and possible mechanisms of G-Re on cardiovascular system.

Chemistry and Content of G-Re Ginsenosides are glycosides that contain an aglycone with a dammarane (except Ro). They are divided into two groups (Figure 1A) based on the type of aglycone, namely the protopanaxadiol (PPD) ginsenoside group (e.g., G-Re and G-Rg1) and the protopanaxatriol (PPT) ginsenoside group (e.g. G-Rb1 and GRc). The aglycone possesses a rigid four trans-ring steroid skeleton with a modified side chain at C-20 [28–34]. According to their biosynthetic pathway and the character reactions, they also belong to triterpenosides with C-30 skeleton. Usually, they occur in Araceae plants as glycosides. The chemical structure of ginsenoside differs from one another by the type of sugar moiety, and the number and site of attachment [30]. During extraction, sugar moieties are cleaved by acid hydrolysis, or by endogenous glycosidases to give the aglycone [33,35,36]. The aglycon, PPD and PPT, may rearrange into panaxadiol and panaxatriol to provide artificial ginsenoside products, respectively. Reports have shown that PPD and PPT ginsenoside groups have different bioactivities, even conversed effects [37,38]. G-Re (Figure 1B) belongs to the PPT group and is one of the major saponins in ginseng [28,37–39]. Xie et al. revealed that the quantity of G-Re in ginseng leaf and berry is much more higher than in ginseng root [40–42]. Overall, G-Re and G-Rd are the major ginsenosides in the ginseng leaf [41,43]. These data show that

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Several reports indicated that G-Re possess protective effects and beneficial functions on the cardiovascular system, such as contractive and electromechanical alternans (EMA) [24,26,38,48], antiarrhythmic effect [26,49], antiischemic activity [50–52], angiogenic regeneration [53,54], and electrophysiological activities of cardiac cells [20–23].

Effect on Cardiac Contractility and EMA The influence of G-Re on cardiac activities includes two aspects: contractility and autorhythmicity. Early study of the effects of GRe on contractility was tested in the rat aorta in vitro [38]. Ginsenosides from the PPT group and its purified G-Re and G-Rg1 cause endothelium dependent relaxation, which is associated with the formation of cyclic GMP. The authors suggested that G-Re and G-Rg1 enhance the release of nitric oxide (NO) from L-arginine in the vascular endothelium and may contribute to the beneficial effect of ginseng on the cardiovascular system. The negative inotropic effects were also obtained in isolated atrial preparation from guinea pig [23,24]. G-Re (4.7 × 10−8 M) decreased the contractile force and frequency of isolated atria with a dose-dependent manner. The significant dose-effects correlation of G-Re on contractility and autorhythmicity of atria model was also observed in this experiment. In addition, G-Re prolonged the effective refractory period of the left atria markedly. G-Re possesses, therefore, negative inotropic and chronotropic effects. The authors suggested that the mechanism of effect of G-Re to decrease the autorhythmicity may be due to the blockage of Ca2+ channels.

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Figure 2 G-Re suppresses mechanical alternans recorded from a human left atrial myocyte. (A): Mechanical alternans induced by electrical pacing (0.75 Hz) at room temperature. (B): steady-state effects of G-Re (1 μM) to suppress alternans and normalize mechanical activity. (C): Washout of G-Re restored alternans (From Wang et al. [45]).

To further ensure the negative effect of G-Re, Scott et al. studied the effect of G-Re and G-Rb1 on cardiac contraction in adult rat ventricular myocytes in vitro. The contractile properties analysis included: peak shortening (PS), time-to-90%PS (TPS), timeto-90% relengthening (TR90), and fluorescence intensity change (DeltaFFI). The results showed that both G-Re and G-Rb1 decreased cardiac contraction in ventricular myocytes. G-Re and G-Rb1 inhibited PS and FFI with a dose-dependent manner (1–1000 nM). The authors also demonstrated that the depressant action of G-Re and G-Rb1 on cardiomyocyte contraction, which may be mediated in part through increased NO production [52]. Aforementioned results further confirmed that G-Re possesses negative effect on cardiac contraction. Wang et al. studied the effect of G-Re on EMA in cat and human cardiomyocytes by using the standard cardiac electrophysiological technology [48]. Figure 2 showed G-Re (1 μM) suppresses mechanical alternans recorded from a human left atrial myocyte. Figure 2(A) shows the mechanical alternans induced by electrical pacing (0.75 Hz) at room temperature. G-Re suppressed alternans and normalized mechanical activity (Figure 2B). The effect of G-Re was reversible and the alternans was restored after washout of G-Re (Figure 2C). The same action of G-Re on EMA was confirmed in Langendorff-perfused cat hearts electrically paced at 2 Hz. Figure 3 showed that G-Re (100 nM) suppresses EMA in a cat ventricular myocyte. Both APD (electrical) alternans (Top) contraction (mechanical) alternans (bottom) were induced by electrical pacing (2 Hz). G-Re (100 nM) markedly suppressed EMA, implying that G-Re not only affects the electrical activity of heart, but also changed the mechanical activity (Figure 3B). EMA was restored after washout of G-Re (Figure 3C) [48].

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Furthermore, the potential cellular mechanisms were investigated in the same group [48]. The results indicated that GRe (≥10 ng) reversibly suppressed EMA recorded from cat ventricular, atrial myocytes, and Langendorff-perfused cat hearts as well. G-Re reversibly suppressed intracellular Ca2+ concentration [Ca2+ ]i transient alternans in cat ventricular myocytes. G-Re suppressed mechanical alternans and exerted no effect on (I Ca,L ) in human atrial myocytes. G-Re increased [Ca2+ ]i transient amplitude and decreased sarcoplasmic reticulum (SR) Ca2+ content, resulting in an increase in fractional SR Ca2+ release in cat ventricular myocytes. The data also indicated that G-Re increased the open probability of ryanodine receptors (RyRs), that is, SR Ca2+ -release channels, isolated from cat ventricles and incorporated into planar lipid bilayers. The research demonstrated that a main biologically active component of G-Re acts via a specific subcellular mechanism to enhance the opening of RyRs and thereby overcome the impaired SR Ca2+ release underlying EMA. However, an opening question remains: why did the G-Re show negative inotropic effect while it increased Ca transient amplitude? The effect of GRe on excitation–contraction coupling remains to be elucidated to answer this question. In fact, alternans, a condition in which there is a beat-to-beat alternation in the electromechanical response of a periodically stimulated cardiac cell, has been linked to the genesis of lifethreatening ventricular arrhythmias [55–57]. Therefore, further experiments are needed to determine how G-Re acts to open RYRs and whether G-Re may serve as a safe and effective drug therapy to reduce the development of arrhythmic activities arising from EMA [48].

Effect on the Cardiac Electrophysiological Properties G-Re and other ginsenosides may exert cardiovascular pharmacological functions through their effects on the electrophysiological properties. An early study [56] on electrocardiogram (ECG) and monophasic action potential (MAP) showed that (1) G-Re (1 mg/kg) shortened the plateau phase of the MAP significantly; (2) G-Re decreased the P-wave in the ECG of the rat dosedependently; (3) P–R, QRS, and Q-Tc intervals and R-wave of ECG, however, did not change significantly. The authors suggested that G-Re may exert more effect on the atria [23]. The electrophysiological effects of G-Re on cardiac and adrenal single cell were studied for comparison with ginseng extracts and ginsenosides [20–22]. Kim et al. reported that the effects of ginseng total saponins (GTS) and single ginsenosides, G-Re, G-Rb1, G-Rc, G-Rf, and G-Rg1 on the inward voltage-dependent Ca2+ currents (I Ca ) and cell membrane capacitance (Cm ) by using whole-cell perforated-patch-clamp technique. GTS and ginsenosides mentioned above exerted inhibitory effects on both I Ca and Cm in rat adrenal chromaffin cells, which are known to release stress hormones. The data suggested that ginsenosides, including G-Re may regulate catecholamine secretion from adrenal chromaffin cells and this regulation could be the cellular basis of antistress effects induced by ginseng extracts and ginsenosides [22]. Bai et al. studied the electrophysiological effects of ginseng extracts and G-Re in ventricular myocytes of guinea pig with the

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Figure 3 G-Re suppresses electromechanical alternans (EMA) in a cat ventricular myocyte (VM). (A): action potentials (Top) and cell shortenings (bottom) recorded during EMA induced by electrical pacing (2 Hz) at room temperature. (B): Steady-state effects of 100 nM G-Re to suppress EMA and normalize both electrical and mechanical activities. (C): Washout of G-Re restored EMA (From Wang et al. [48]). 141 × 61 mm.

whole-cell patch clamp technique. The data showed that ginseng extracts (1 mg/ml) shortened the action potential duration (APD) significantly in a rate-dependent manner [20]. This result is consistent to early MAP study described above [23,56]. The authors further explored the effects of ginseng and G-Re on whole-cell currents. Application of 1 mg/ml ginseng depressed the L-type Ca2+ current (I Ca,L ), and enhanced the slowly activating component of the delayed rectifier K+ current (I Ks ), while it exerted no effect on inward rectifier potassium current (I K1 ). G-Re (3.0 μM) exhibited similar electrophysiological activities to those of ginseng extract. The inhibition of I Ca,L and enhancement of I Ks by G-Re appear to account for main electrophysiological actions of ginseng in the heart, although contribution from other ingredients cannot be excluded. G-Re enhances the slowly activating component of the I Ks and suppresses I Ca,L , which may account for APD shortening [20,21]. Thus, G-Re may protect the heart against I/R injury by shortening APD and thereby prohibiting influx of excessive Ca2+ . The same group further defined the mechanism of enhancement of I Ks and suppression of I Ca,L by G-Re in guinea pig ventricular cells [21]. Their results indicated that G-Re–induced I Ks enhancement and I Ca,L suppression involve NO actions. Direct Snitrosylation of channel protein appears to be the main mechanism for I Ks enhancement, while a cGMP-dependent pathway is responsible for I Ca,L inhibition. Recent studies by the same research group further revealed that G-Re acted as a specific agonist of androgen receptors and activated the nongenomic pathway. The NO release form endothelial NO synthase activated I Ks . These electrophysiological effects of G-Re on ion channels may exert cardiac protective effects against I/R injury [58].

tricular arrhythmia. The histopathologic examination also demonstrated that G-Re (20 and 10 mg/kg) treatment ameliorated myocardial injuries induced by triggered ventricular arrhythmias. The antiarrhythmic effect of G-Re was also observed in other experiments in vitro. The determination of the pharmacological influence of G-Re on isolated cat and human ventricular myocytes was performed by using whole-cell patch clamp to record Na+ current (I Na ), L-type Ca2+ current (I Ca,L ), and K+ current (I K ) [26]. Stimulated (1 Hz) action potentials (APs) and cell shortening were recorded simultaneously. The results showed that the exposure to G-Re (10 μM) decreased action potential duration (APD90 : 232 ± 12 vs.194 ± 7 ms) and cell shortening significantly (3.9 ± 0.6 vs. 2.7 ± 0.5 μm, P < 0.05). The data also indicated that myocytes exposed to low (0.5 mM) extracellular (Mg2+ ) and low (2.2 mM) extracellular (K+ ) to elevate intracellular (Ca2+ ), responded to short trains of rapid pacing with delayed afterdepolarizations (DADs) and spontaneous APs. G-Re suppressed pacinginduced DADs and spontaneous APs (n = 7). They concluded that G-Re exerts significant antiarrhythmic actions in cat ventricular myocytes. The antiarrhythmic effects of G-Re may act at intracellular sites that regulate Ca2+ homeostasis. Overall, G-Re has the antiarrhythmic effect, which may lead to its pharmacological development in the cardiac arrhythmic treatment. However, the mechanism of its antiarrhythmic effect is still obscure and more studies are required to provide further evidence, especially the relevant clinic trials will give us much more valuable information.

Antiischemic and Cardioprotective Effect Antiarrhythmic Effect To explore the antiarrhythmic effect of ginsenosides, the protective action of G-Re on isoproterenol-induced triggered ventricular arrhythmia was studied in rabbit heart in vivo [49]. The data indicated that G-Re (20, 10, and 5 mg/kg) and verapamil (0.4 mg/kg) treatment restored sinus rhythm from isoproterenol-induced triggered ventricular arrhythmia. The durations of sinus rhythm were 177.0 ± 5.7 sec and 177.8 ± 5.3 sec in the verapamil treatment group and in the G-Re (20 mg/kg) treatment groups, respectively (P > 0.05 compared between two groups). Therefore, both verapamil and G-Re possess antagonistic activity for triggered ven-

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The effects of G-Re on cardiomyocyte apoptosis and expression of Bcl/Bax gene after ischemia (30 min) and reperfusion (6 h) were observed in Wistar rats [50]. The apoptotic cardiomyocytes were confirmed by transmission electron microscopy and counted by in situ nick end labeling method and light microscopy. The mRNA and protein expression of Bcl-2 and Bax genes were studied by in situ hybridization and immunohistochemical staining. Mean optical density value of the positive fields of mRNA and protein expression was quantitatively examined by image analysis system. The results indicated that: (1) The apoptotic cardiomyocytes were found in ischemic fields of the ischemia/reperfusion (I/R) group, but weren’t observed in the sham-operation group by

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transmission electron microscopy; (2) The numbers of the apoptotic cardiac cells in the G-Re–treated group were decreased significantly compared with the sham-operation group (P < 0.01); (3) Gene expression of Bcl-2 and Bax were increased markedly in the ischemia/reperfusion group. The ratio of Bcl/Bax was increased significantly in the G-Re–treated group compared with the I/R group and sham-operation group. These data suggested that myocardial ischemia/reperfusion induces cardiac cell apoptosis obviously, and G-Re significantly inhibits cardiac cell apoptosis induced by I/R in rats. The authors concluded that G-Re inhibits cardiomyocyte apoptosis by decreasing expression of proapoptotic Bax gene and raising the ratio of Bcl-2/Bax. In addition, Chen et al. studied the effects of G-Re on the cerebral ischemia/reperfusion damage in vivo [51]. They investigated the neuroprotective potential of G-Re (10, and 20 mg/kg) by using the middle cerebral artery occlusion model in rat. Cerebral I/R injury produced a significant increase in the neurological score, indicating neurological dysfunction. The neurological score was increased in the vehicle group (4.20 ± 0.42, P < 0.001 compared with the sham group). The elevated neurological score was significantly reduced (3.50 ± 0.53, P < 0.01 and 1.70 ± 0.48, P < 0.001, compared with the vehicle group) after 10 and 20 mg/kg G-Re administration, respectively. They also observed that the level of malondialdehyde (MDA) in ischemic animals (indicating oxidative stress) increased significantly. After treatment of G-Re group, however, MDA reduced markedly compared to control group. G-Re decreases mitochondrial swelling, thereby G-Re may prevent the reduction of H+ -ATPase activity. The authors suggested that G-Re exhibited significant protection against cerebral ischemia/reperfusion injury.

hemoglobin content in the ECMs were significantly enhanced by G-Re. These data demonstrated that like bFGF, G-Re–associated induction of angiogenesis enhanced tissue regeneration, supporting the concept of therapeutic angiogenesis tissue-engineering strategies. Another work further confirmed the angiogenic effects of ginsenosides [54]. The observation showed that G-Re and G-Rg1 enhanced the angiogenesis both in vitro and in vivo by the similar methods above. In the in vitro experiments, human HUVEC proliferation, migration in a transwell plate, and tube formation on matrigel were all significantly enhanced in the presence of G-Re, and G-Rg1. In the in vivo experiments, the results observed on day 7 after the implantation showed that the blank control (Matrigel alone) was slightly vascularized. In contrast, the density of neo-vessels in the Matrigel plug mixed with G-Re, and G-Rg1 was significantly enhanced. As aforementioned, the authors suggested that G-Re and G-Rg1 could be a novel group of nonpeptide angiogenic agents with a superior stability and may be used for the management of tissue regeneration.

Conclusions G-Re belongs to the panaxatriol group and is one of the major ginsenoside in ginseng. G-Re possesses many beneficial and pharmacological effects on cardiovascular system, such as negative effect on cardiac contractility and EMAs, antiarrhythmia, angiogenic regeneration, and on the cardiac electrophysiological function. These beneficial properties on cardiovascular system may provide an opportunity to develop new treatment agents if these data can be validated in future clinical trials.

Effect on Angiogenic Regeneration

Acknowledgements

The effect of G-Re on angiogenic regeneration for tissue was investigated in human umbilical vein endothelial cell (HUVECs) in vitro and extracellular matrix (ECM) in rat model [53]. Basic fibroblast growth factor (bFGF) was used as a control in this experiment. It was found that HUVEC proliferation, migration in a transwell plate, and tube formation on matrigel were all significantly enhanced in the presence of G-Re with a dose-dependent manner. The angiogenesis in the ECMs was significantly enhanced by loading with G-Re. The in vivo experiments at 1 week postoperatively showed that the density of neocapillaries and the tissue

LHX is supported by NIH/NHLBI R01 HL97979.

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Author Contributions All authors contributed to literature searching, discussion, critical appraisal, writing, and revising the manuscript.

Conflict of Interest The authors have no conflict of interest.

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