Canadian Journal of Physiology and Pharmacology · Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp-2018-0192.R1 Manuscript Type: Review Date Submitted

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Cardioprotection by Ginseng: Experimental and Clinical

Evidence and Underlying Mechanisms

Journal: Canadian Journal of Physiology and Pharmacology

Manuscript ID cjpp-2018-0192.R1

Manuscript Type: Review

Date Submitted by the Author: 04-Jun-2018

Complete List of Authors: Gan, Tracey; Uiniversity of Western Ontario Karmazyn, Morris; University of Western Ontario

Is the invited manuscript for consideration in a Special

Issue: Not applicable (regular submission)

Keyword: Ginseng, ginsenosides, myocardial ischemia and reperfusion, cardiac

protection

https://mc06.manuscriptcentral.com/cjpp-pubs

Canadian Journal of Physiology and Pharmacology

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Cardioprotection by Ginseng: Experimental and Clinical

Evidence and Underlying Mechanisms

Xiaohong Tracey Gan and Morris Karmazyn1

University of Western Ontario, London, Ontario, Canada N6G

2X6

1 Retired

Corresponding author: [email protected]

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Abstract

Protection of the ischemic and reperfused myocardium represents a major therapeutic challenge.

Translating results from animal studies to the clinical setting has been disappointing, yet the need

for effective intervention particularly to limit heart damage following infarction or surgical

procedures such as coronary artery bypass grafting is substantial. Among the many compounds

touted as cardioprotective agents is ginseng, a medicinal herb belonging to the genus Panax

which has been used as a medicinal agent for thousands of years, particularly in Asian societies.

The biological actions of ginseng are very complex and reflect composition of many bioactive

components although many of the biological and therapeutic effects of ginseng have been

attributed to the presence of steroid-like saponins termed ginsenosides. Both ginseng as well as

many ginsenosides have been shown to exert cardioprotective properties in experimental models.

There is also clinical evidence that traditional Chinese medications containing ginseng exert

cardioprotective properties although such clinical evidence is less robust primarily owing to the

paucity of large scale clinical trials. Here, we discuss the experimental and clinical evidence for

ginseng, ginsenosides and ginseng-containing formulations as cardioprotective agents against

ischemic and reperfusion injury. We further discuss potential mechanisms, particularly as these

relate to antioxidant properties.

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Introduction

Research into cardiac protection has been, and continues to be one of the most, if not the most,

active research areas in the cardiovascular field with thousands of papers published. The reason

for such high research activity is not difficult to understand since reducing myocardial damage

and infarct size following infarction is associated with improved long-term prognosis and

reduced risk for the subsequent development of heart failure. Research spanning nearly four

decades and encompassing various experimental models (see below) has identified a large

number of both pharmacological and non-pharmacological approaches to limit cardiac muscle

damage, indeed with a great deal of efficiency at least as seen in experimental studies. Table 1

presents a very limited list of interventions that have shown promise over the years as potentially

effective cardioprotective strategies. Unfortunately, robust experimental data have not translated

into clinical efficacy, which has recently been referred to as a “remarkable record of failure”

(Lefer and Marban 2017). As recently reviewed by Binder et al. (2015) many reasons have been

proposed for these disappointing clinical results and the failure to translate animal data to the

clinical scenario.

Ginseng has been used as a therapeutic agent for a large number of medical disorders for

thousands of years, particularly in Asian societies. Ginseng is a complex natural compound

belonging to genus Panax, family Araliaceae, represented by various species and containing

many bioactive constituents such as the steroid-like saponins named ginsenosides which are

thought to be largely but not exclusively responsible for ginseng’s therapeutic properties.

Although it is beyond the scope of this review to discuss the general chemical and biochemical

properties and characteristics of ginseng species, a number of reviews dealing with these issues

can be recommended (Lü et al. 2009; Yamasaki 2000; Yuan et al. 2010; Qi et al. 2011).

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Moreover, a recent review focuses on the chemistry, structure, nomenclature and therapeutic

properties of individual ginsenosides (Kim et al. 2017). We have recently reviewed in this

Journal the potential benefits of ginseng and ginseng-related products to limit myocardial

remodelling and heart failure (Karmazyn and Gan 2017). Here, we focus on another potential

benefit of ginseng and assess the evidence regarding the direct cardioprotective effects of

ginseng, ginsenosides and ginseng-containing products against ischemia and reperfusion induced

myocardial injury from both experimental and clinical studies. To fully appreciate the bases for

this it is important to understand the experimental models which have been used to identify

potentially effective cardioprotective agents as discussed in the following section.

Experimental models to identify cardioprotective agents

Both in vivo and in vitro techniques have been used extensively in the search for identifying

potentially effective cardioprotective strategies. The latter are basically the simplest approaches

in which isolated cardiomyocytes or cardiac tissues are subjected to ischemic and reperfusion

conditions generally by treating these preparations with hypoxic and then oxygenated media with

various compositions. As reviewed by Yellon and Hausenloy (2007), the reperfusion component

is of paramount importance in view of the well-established concept that reperfusion of the

ischemic heart represents an exacerbation and acceleration of already-existing ischemic induced

injury. This so-called reperfusion injury has substantial clinical relevance since myocardial

reperfusion with various means such as using thrombolytic agents, angioplasty or surgical

revascularization represents a critical treatment of patients who have suffered a myocardial

infarction (Bassand et al. 2005). Interestingly though, the nature of reperfusion injury appears to

be quite distinct from injury observed during the initial ischemic insult and protecting the

reperfused heart has also materialized into a major clinical challenge (Yellon and Hausenloy

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2007). Ideally, an effective cardioprotective agent is one which attenuates myocardial injury

when administered at the time of reperfusion. Certainly, such treatments would have major

clinical usefulness since they can potentially be administered to patients following infarction.

Thus, limitation of reperfusion injury represents an important therapeutic target. However,

limiting ischemic injury, that is injury occurring prior to reperfusion is also of benefit

particularly under circumstances such as coronary artery bypass surgery when effective

cardioprotective agents can be administered prior to the surgical procedure therefore protecting

the heart during induced ischemia (Mentzer Jr 2011). A summary of the phases of injury

occurring during myocardial ischemia and reperfusion is illustrated in Figure 1 in relation to the

key role of sodium-hydrogen exchange isoform 1 (NHE-1). Activation of NHE-1 can lead to

intracellular calcium overload through the sodium-calcium exchanger (NCX) resulting in

activation of processes that result in apoptotic or necrotic cell death. Thus, timely early

reperfusion before the onset of these processes can prevent cell death concomitant with

functional recovery (reversible ischemia).

In vitro models

The use of isolated cells and tissues ex vivo presents several advantages as these models preclude

the possible contribution of neuronal and hormonal factors to the injury process thus simplifying

the model and providing a better opportunity to study intrinsic mechanisms mediating injury

(Maddaford et al. 1999). However, such approaches are also potentially limited in terms of

physiological and clinical relevance since they do not represent ischemia and reperfusion per se

but rather conditions associated with ischemia and reperfusion such as hypoxia and

reoxygenation. Nonetheless, Portal et al. (2013) have recently shown that freshly isolated mouse

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cardiomyocytes can exhibit a similar profile of injury when subjected to hypoxia and

reoxygenation as that seen under in vivo conditions.

More clinically relevant ex vivo models are the isolated freshly perfused heart, the so called

Langendorff preparation (Döring 1990) or the Neely working heart (Neely et al. 1967) which are

perfused through the coronary arteries, either retrogradely or antegradely respectively, with

either simple saline buffers or complex media and which can then be subjected to actual

ischemia and reperfusion using various techniques. Even though these experimental models

have provided a plethora of valuable information, as with most ex vivo preparations results

obtained using these techniques should be interpreted with caution primarily as these

preparations are generally devoid of hormonal or neuronal influence or indeed influence by other

critical blood-borne factors (Hearse and Sutherland 2000).

In vivo models

As reviewed by Black (2000) cardioprotective strategies can also be studied and assessed using

in vivo live animal models. In most cases this involves subjecting animals to coronary artery

ligation with reperfusion and determining the modulation of infarct sizes by treatment. Several

animal species have been studied using this approach although rats and dogs predominate as

animals of choice to determine infarct sizes in vivo. However, with the development of genetic

mouse models of heart disease there has been increasing interest in the use of the coronary artery

ligation infarction model in this species (Gao et al. 2010). Experimental coronary artery ligation

offers an additional advantage as infarct sizes can be readily manipulated simply by altering the

duration of the coronary artery ligation period. Moreover, as a general rule the degree of

reperfusion injury, that is injury occurring after restoration of coronary flow, is dependent on the

duration and therefore the severity of the preceding ischemic period (Figure 1).

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As summarized in Table 1, studies using such diverse experimental models have revealed a

plethora of experimental approaches including pharmacological agents as well as procedures

such as ischemic preconditioning (brief sub-lethal cycles of ischemia prior to prolonged

ischemia) and postconditioning (brief cycles of ischemia following prolonged ischemia and

before reperfusion) as effective cardioprotective strategies experimentally but these have

generally proved disappointing when applied to patients. One of the potential reasons for this is

the fact that most experimental animal studies may be poorly applicable to the human population

as the former generally employed young animals with no co-existing morbidities, in contrast to

what is seen with cardiac patients who are generally in the older age bracket and who often

present with other clinical conditions with both factors potentially confounding effective

cardioprotection. Another basis for disappointing translational results may lie with the fact that

mechanisms of ischemia- and reperfusion-induced cardiac injury are distinct as well as complex.

Thus, focussing on the best appropriate target(s) as well as ideal timing of treatment are likely of

paramount importance. With respect to the latter this represents a major challenge as

administering a cardioprotective strategy after infarction, that is at the time of reperfusion, may

have limited value in view of the fact that substantial cell death has already occurred prior to

initiation of treatment (Schaper and Schaper 1988). Limiting damage, particularly that produced

by reperfusion may therefore represent a challenging goal in the setting of acute myocardial

infarction. As alluded to above, a clinical scenario where cardiac protection efficacy could be

tested under more controlled environment is in high risk patients undergoing coronary artery

bypass grafting (CABG) since in these patients treatment can be initiated during ischemia (i.e.

cardiac arrest during surgery) as well as reperfusion following completion of the surgical

procedure (Mentzer Jr 2011). Cardioprotection was indeed observed in high risk CABG patients

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who were administered the NHE-1 inhibitor cariporide although any potential clinical

development of this agent was negated by the unexpected increased occurrence of

cerebrovascular thromboembolic events (Mentzer et al. 2008).

Mechanisms of injury

A complicating factor in designing effective cardioprotective strategies likely also reflects the

complexity of mechanisms underlying injury and cell death. From a general perspective cell

death can occur from both necrosis as well as apoptosis, also referred to as “programmed cell

death” with each mode of death reflecting distinct mechanisms of injury (Fink and Cookson

2005). Although they share some common mechanisms, cardiac injury and cell death occurring

as a consequence of ischemia are quite different and distinct from reperfusion injury occurring

following post-infarction restoration of blood flow. Although it is beyond the scope of this

review to discuss the underlying complex mechanisms of ischemia- and reperfusion-induced

injury in substantial detail various excellent reviews can be recommended (Binder et al. 2015;

Yellon and Hausenloy 2007; Mentzer Jr 2011; Hausenloy and Yellon 2015). Briefly, it is

appropriate to state that defective intracellular ion regulation especially that occurring during

prolonged ischemia is a prerequisite for irreversible ischemic injury, intracellular calcium

dysregulation as evidenced by elevations in intracellular calcium levels represents a major

contributor to this process (Opie 1991). Thus, as illustrated in Figure 1, a major goal of

mitigating ischemic-induced injury involves the inhibition of intracellular calcium overload and

preventing the transition from reversible to irreversible injury (Opie 1991). While reperfusion-

induced injury also reflects complex intracellular events, a major contributing factor to this type

of injury is the rapid reintroduction of oxygen upon early reflow thus leading to the generation of

reactive oxygen species (ROS) resulting in myocyte injury (Maddika et al. 2009;

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Braunersreuther and Jaquet 2012). Therefore, inhibitors of ROS generation as well as free radical

scavengers have generally proven effective in experimental models of reperfusion injury, both in

vitro and in vivo. The beneficial consequences of inhibiting ROS generation and attenuating

intracellular calcium dyshomeostasis are multifold although one of the major consequences

which can greatly attenuate the degree of injury is inhibition of the mitochondrial permeability

transition pore (mPTP) in the inner mitochondrial membrane whose activation results in

subsequent loss of ionic homeostasis, matrix swelling, outer membrane rupture and the

development of apoptosis (Javadov and Karmazyn 2007). Indeed, as will be evident below,

inhibition of oxidative stress as well as intracellular calcium abnormalities appear to be some of

the primary mechanism underlying the cardioprotective effects of ginseng-related compounds.

Although marked ischemia- and reperfusion-induced injury can be achieved using in vitro

preparations, it should be noted that mechanisms contributing to such injuries are markedly more

complex in vivo. This is principally due to the fact that extracardiac factors contribute to

myocardial injury as well. A primary example of this, as demonstrated many years ago, would

be the accumulation and infiltration of neutrophils in the ischemic area which can then release a

myriad of cardiotoxic compounds such as ROS and other pro-inflammatory mediators (Williams

1996; Jordan et al. 1999). Indeed, inhibition of neutrophil accumulation and function represents

an effective cardioprotective strategy in the experimental setting.

Assessment of injury and cardioprotective efficacy

As will be evident when describing individual examples below, there are a number of

determinations one can undertake to assess the degree of injury using the various experimental

models that have been referred to. For example, the degree of cardiomyocyte injury can be

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determined indirectly by assessing the release of enzymes such as creatine kinase (CK) or lactate

dehydrogenase (LDH) as well as Troponin I which can then be measured either in the

bloodstream for in vivo studies or in superfusion or perfusion media for ex vivo models of

ischemia- and reperfusion-induced injury (Singh et al. 2010). Moreover, injury can be assessed

histologically to directly determine the degree of damage or by cell viability assays, the latter of

particular usefulness when using myocyte preparations. These approaches do not effectively

differentiate between necrotic or apoptotic cell death which have substantially different

characteristics and which contribute in their individual ways to mediate myocardial injury

(Kajstura et al. 1996). A large number of assays are available which can measure apoptosis by

determining the levels of specific enzymes and factors which are involved in the apoptotic

process as well as apoptosis-specific injury including DNA fragmentation as determined by TdT-

mediated dUTP-biotin nick end-labeling (TUNEL) staining (Darzynkiewicz et al. 2008). Cardiac

function is also of substantial benefit as an index of degree of injury or protection by

interventions particularly when using experiments involving intact heart preparation either in

vivo or in isolated tissues.

Evidence for ginseng, ginsenosides and ginseng-related products as

cardioprotective agents

Ginseng species

The potential cardioprotective properties of ginseng have been known for at least two decades

with the finding that Trilinolein, a triacyglycerol purified from P pseudoginseng, an atypical

member of the Panax species, protected the isolated rat heart against ischemia, an effect which

was associated with preserved mitochondrial structure, a benefit attributed to antioxidant

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properties of this compound as well as maintenance of membrane fluidity and inhibition of

calcium influx (Chan et al. 1996, 1997).

Thus, the antioxidant properties of ginseng and its ginsenosides appear to be an important factor

in mediating their cardioprotective actions. This has been demonstrated directly in myocytes

exposed to a free radical generating system to generate the superoxide anion or by the addition of

exogenous ROS and where cell death under these conditions was markedly reduced by berry

extracts of P quinquefolius or North American ginseng (Shao et al. 2004; Mehendale et al. 2005).

Interestingly, in one of these studies (Shao et al. 2004) the efficacy of the P quinquefolius berry

extract was greater than that seen with extract taken from the ginseng root, suggesting that the

former has a greater antioxidant property. It has also been reported (Sui et al. 2001) that P

quinquefolius leaf extracts, specifically 20s-protopanaxdiol saponins, reduce infarct size through

an antioxidant mechanism in dogs subjected to acute myocardial infarction (Sui et al. 2001).

However, numerous other targets may also be involved such as reduction in endoplasmic

reticulum stress as shown for P quinquefolius which was associated with reduced apoptosis (Xue

et al. 2013; Liu et al. 2013, 2015), inhibition of platelet aggregation either when tested alone

(Xue et al. 2015) or in combination with established antiplatelet agents (Wang et al. 2015) as

well as the regulation of a large number of genes and proteins involved in numerous aspects of

myocardial homeostasis as has been proposed for P notoginseng as well as ginseng-containing

formulations (Yue et al. 2012; Wang et al. 2013; Zhu et al. 2013). Moreover, P notoginseng has

been shown to enhance mobilization of C-kit+ bone mesenchymal stem cells in rats subjected to

myocardial infarction thus potentially enhancing post-infarction myocardial repair (Zhang et al.

2011) as well as to reduce oxidative stress and inflammation (Han et al. 2013). P ginseng, also

referred to as Asian ginseng, has also been shown to reduced infarct size in a rat infarction model

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through a mechanism involving preservation of PI3K and serine/threonine protein kinase Akt

(protein kinase B) levels in the myocardium which are important components of the so-called

myocardial salvage pathway (PI3K-Akt) resulting in increased NO production via eNOS

activation thus representing a potential additional important target site for ginseng-related

protection (Pei et al. 2013; Zhou et al. 2011). Interestingly, as discussed below, activation of this

pathway has been proposed as a mechanism of action for various individual ginsenosides. Guo

et al. (2009, 2010) have proposed an antioxidant effect of P notoginseng in a rat acute

myocardial infarction model which could be due to decreased cytokine production.

Lim et al. (2013, 2014) have reported that Korean red ginseng (P ginseng subjected to a heating

process) administration exerts cardioprotective effects against isoproterenol-induced injury as

well as electrophysiological changes in rats in the absence of any changes in heart rate thus

implicating a direct cardioprotective effect. In these studies, it was proposed that the salutary

effect of Korean red ginseng was due primarily to an antioxidant effect similar to that seen in

studies using ischemia models of injury.

The salutary effect of ginseng has also been found to occur in older animals, a potentially

important finding as virtually all studies assessing cardioprotection have been carried out using

young subjects. For example, Luo et al (2015) have shown that administering a P ginseng

extract for 90 days to aged (18 months old) rats prior to induction of acute coronary artery

ligation and reperfusion reduced infarct size, indices of apoptosis, and improved left ventricular

function and survival. Several mechanisms were proposed for this protection including the

stimulation of the salvage pathway, referred to above as well as two sirtuin isofoms (Sirt1 and

Sirt3) which are known to play important roles in cell homeostasis leading overall to reduced

apoptosis (Luo et al. 2015).

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A summary of the cardioprotective effects of different ginseng species as well as ginsenosides,

compound k and ginseng-containing formulations which are discussed in the following sections

is presented in Table 2.

Ginsenosides

Both total saponin extracts as well as individual ginsenosides have been shown to exert

cardioprotective effects. For example, cardioprotection has been documented with individual

ginsenosides such as ginsenoside Re which attenuated hydrogen peroxide-induced toxicity in

chick cardiomyocytes thus demonstrating an antioxidant property (Xie et al. 2006). However,

other mechanisms may also be at play with this particular ginsenoside such as enhancing

endothelial nitric production by activating eNOS: it has been shown that this effect is associated

with cardiac potassium channel activation thus mitigating ischemia-reperfusion injury (Furukawa

et al. 2006). It is interesting that in this study it was shown that ginsenoside Re releases NO via a

nongenomic pathway involving sex steroid receptor activation resulting in potassium channel

activation in cardiac myocytes (Furukawa et al. 2006). Indeed, ginsenoside Re has been shown

to exert several electrophysiological effects on the cardiac cell conducive to cardiac protection in

addition to targeting potassium channels including the inhibition of calcium channels, also via

increased NO generation (Bai et al. 2003, 2004). In addition, various groups (Wang et al. 2009a;

Yin et al. 2005; Xu et al. 2013) have reported that P quinquefolius saponin extracts produce a

reduction in cardiac injury including an attenuation of apoptosis by directly modifying apoptosis-

regulating factors, improving function and decreasing oxidative stress in both myocytes as well

as hearts subjected to coronary artery ligation. As noted above, a potential mechanism may also

involve the inhibition of mPTP opening. Thus, administering a P quinquefolius saponin extract

for four weeks to rats prior to ischemia and reperfusion produced a significant reduction in

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infarct size associated with mitochondrial protection likely associated with inhibition of mPTP

opening (Li et al. 2014). These saponins have also been proposed to exert beneficial effects in

infarcted rat hearts by promoting coronary angiogenesis through the upregulation of expression

of proangiogenic growth factors (Wang et al. 2007), an effect similarly observed for saponin

extracts from the flower buds of P notoginseng (Yang et al. 2016).

Several other ginsenosides have also been shown to exert protective effects through a number of

proposed mechanisms. For example, Zhu et al. (2009) have shown that ginsenoside Rg1

improved cell viability in cardiomyocytes exposed to hypoxia reoxygenation through an

antioxidant effect as well as a reduction in intracellular calcium levels. Rg1 also protected H9c2

cells (a cardiomyoblast cell line) against hypoxia and reoxygenation induced injury through a

proposed mechanism involving heme oxygenase-1 (HO-1) upregulation and inhibition of c-Jun

N-terminal kinases (JNK) activation (Li et al. 2017a). Deng et al. (2015) showed that Rg1 also

improved cardiac function in rats subjected to infarction in which Rg1 was co-administered with

salvianolic acid B, extracted from the herb Salvia miltiorrhiza, although no benefit was seen in

ginsenoside Rb1 treated animals. However, the lack of benefit seen with ginsenoside Rb1is in

contrast with other studies showing robust cardioprotection with Rb1 treatment. Indeed, it is

interesting that a single intravenous administration of Rb1 ten minutes before subjecting rats to

45 minutes of coronary artery occlusion and two hours reperfusion reduced cardiac injury

suggesting a preconditioning-like effect of this ginsenoside (Wang et al. 2008). The benefit

exerted by Rb1 was associated with increased Akt (protein kinase B) phosphorylation, which as

already noted is an important component of the so-called myocardial salvage pathway (PI3K-

Akt). Moreover, Wang et al. (2008) have reported that Rb1-mediated protection was abolished

by wortmannin, a non-specific PI3K inhibitor. Generally similar effects were seen in ischemic

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and reperfused hearts from diabetic rats treated with Rb1 (Wu et al. 2011) an effect which may

also involve increased production of endothelial-dependent NO via eNOS upregulation (Xia et

al. 2011). Improved cardioprotection for both ginsenoside Rb1 and Rg1 was shown to occur

when the ginsenosides were administered to rats within core-shell liposomal vehicles in order to

improve bioavailability (Zhang et al. 2012). In that study improved protection was seen in both a

cerebral model of ischemia and reperfusion as well as myocardial ischemia produced by

administering the pituitary gland extract pituitrin, which consists primarily of vasopressin and

oxytocin (Zhang et al. 2012). It appears that Rb1 exerts cardioprotective effects through a

plethora of mechanisms. For example, in addition to the various mechanisms just noted,

ginsenoside Rb1 has recently been proposed to protect the heart by inhibiting succinate

accumulation in both ischemic and reperfused working rat hearts as well as hypoxic and

reoxygenated cardiomyocytes (Li et al. 2017b). This resulted in improved activity of pyruvate

dehydrogenase through inhibition of succinate-associated HIF-1α activation and GPR91

signaling resulting in attenuated cardiac acidification, improved mitochondrial dysfunction and

reduced apoptosis (Li et al. 2017b). Cui et al. (2017) also showed that Rb1 exerted several

salutary effects in rats subjected to 30 minutes coronary artery ligation followed by 90 minutes

of reperfusion including reduced infarct size, apoptosis and improving cardiac function. These

effects were attributed to an ability of Rb1 to directly inhibit RhoA thus preventing RhoA-

dependent cell signalling and improving ATP preservation. Interestingly, an identical mechanism

has been proposed for the cardioprotective effects of ginsenoside Rg1 when administered to rats

subjected to 30 minutes of coronary artery occlusion followed by 90 minutes of reperfusion (Li

et al. 2018).

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Shi and coworkers (2011) demonstrated cardioprotection with the ginsenoside Rb3 which

reduced infarct size when administered to rats prior to acute coronary artery occlusion and

reperfusion. This salutary effect was associated with reduced indices of oxidative stress in the

left ventricle as determined by diminished levels of malondialdehyde and decreased superoxide

dismutase activity (Shi et al. 2011).

Ginsenoside Rg5, an important component of heated ginseng has also been shown to increase

resistance to hypoxia and reoxygenation induced injury of neonatal rat ventricular myocytes by

reducing mitochondrial damage. Yang et al. (2017) have demonstrated that this occurs through

the regulation of translocation of two important enzymes, namely hexokinase II, the principal

hexokinase isoform in the heart as well as the mitochondrial fission protein Dynamin related

protein 1, generally referred to as DRp1.

It is interesting that in a study using a metabonomic approach, a combination of the ginsenosides

Rg1 and Rb1 failed to substantially improve myocardial metabolic status when administered to

rats for seven days following induction of myocardial infarction (Jiang et al. 2014). However,

marked improvement was seen when these ginsenosides were administered in combination with

other purported bioactive compounds found in the Chinese Traditional Medicine Sheng-Mai San

including schizandrin and ophiopogonin D (Jiang et al. 2014). While the finding of lack of

efficacy of the ginsenosides was surprising, the study nonetheless reinforces the concept that

ideal cardioprotective benefit of ginseng will likely be particularly evident when used as

adjunctive therapy with other medications.

There is good evidence that in vivo treatment with ginseng-related compounds bestows

subsequent protection ex vivo. For example, administering either total or purified (panaxadiol or

panaxatriol) saponins to rats for seven days resulted in subsequent protection of excised isolated

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perfused hearts which were then subjected to ischemia and reperfusion as demonstrated by

improved function, attenuation of cell damage concomitant with a reduction in oxidative stress,

the latter proposed as the primary basis for the salutary effects of these compounds (Kim and Lee

2010; Aravinthan et al. 2015). Han et al. (2013) showed a similar beneficial effect in rats

subjected to coronary artery occlusion and reperfusion that were administered P notoginseng.

This study also showed that the benefit could be enhanced with coadministration of extracts of

the Safflower plant (Cartharmus tinctorius L) thus suggesting that combination therapy could

effectively enhance the cardioprotective effect of ginseng-related compounds. Furthermore,

seven-day pretreatment with a saponin extract from P japonicas exerted substantial protection in

rats subjected to 12 hours of coronary artery ligation, without reperfusion, as manifested by

improved function, reduced injury including apoptosis as well as reduced markers of oxidative

stress and expression levels of cytokines (He et al. 2012; Wei et al. 2014).

It is clear from the evidence that there is substantial variability in terms of efficacy of various

ginsenosides as cardioprotective factors. Such variability may reflect the experimental model

used or, as recently proposed, the chemical structure of the ginsenoside species. With respect to

the latter Feng et al. (2017) recently suggested that compounds lacking the hydroxide group at

C6 may be more effective, at least in terms of reducing apoptosis in H9c2 cells (a

cardiomyoblast cell line) subjected to hypoxia and reoxygenation although it remains to be

determined whether this concept can be applied to other experimental models.

Thus, when taken together it appears that ginsenosides exert salutary effects through multiple

mechanisms although many of these ginsenosides share the ability to activate the PI3K-Akt

pathway resulting in increased NO production secondary to eNOS activation. How this

specifically occurs is not known although as proposed in Figure 2, one possible mechanism may

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involve the stimulation of receptor tyrosine kinase (RTK) by individual ginsenosides which

results in eNOS activation secondary to stimulation of protein kinase Akt (Fulton et al. 1999; Liu

et al. 2014). This hypothesis needs to be assessed with further studies particularly since various

ginsenosides such as Rg3 may activate a number of cell signalling pathways which result in

eNOS upregulation (Hien et al. 2010).

Compound K: a bioactive ginsenoside metabolite

The ginseng metabolite compound K (20-O-(β-D-glucopyranosyl)-20(S)-protopanaxadiol),

formed via biotransformation of a number of ginsenosides by intestinal bacteria, also exerts

cardioprotective properties. Tsutsumi and coworkers showed that compound K administration to

mice reduced infarct size and calcium-induced mitochondrial swelling following ischemia and

reperfusion in vivo which was associated with enhanced Akt and eNOS activities as discussed

above for ginsenoside Rb1 (Tsutsumi et al. 2011). These findings further implicate the

involvement of the PI3K-Akt myocardial salvage pathway as a potential key target for the

cardioprotective effects of numerous ginseng-related products.

Ginsenoside-containing preparations

Complex preparations containing ginsenosides have also been studied as cardioprotective agents,

many of which are in common use for the treatment of coronary heart disease in Asian countries

(Hung et al. 2015). One of these herbal medications, Shenfu, is currently used in Asian societies,

particularly China, as treatment for cardiovascular diseases as well as other conditions. Wang et

al. (2009b) have reported that Shenfu reduces apoptosis in cardiomyocytes exposed to hypoxia

and reoxygenation, an effect which was associated with increased expression of the antiapoptotic

protein B-cell lymphoma 2 (Bcl-2) and a concomitant decrease in pro-apoptotic caspase-3

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activation. Shenfu has also been shown to reduce infarct size when administered to rats prior to

induction of myocardial infarction produced by coronary artery ligation followed by reperfusion

likely due to antioxidant effects of the formulation (Zheng et al. 2004).

Another similar formulation, Sheng-mei-san, consisting of Radax ginseng plus other constituents

including Fructus schisandrea has been studied for its cardioprotective properties. Li et al.

(1996) have postulated that the presence of lignan-enriched extract of Fructus schisandrae

accounts for the beneficial effects of Sheng-Mai-San although others have implicated the

ginsenoside content of this formulation as a basis for cardioprotection, at least in a mouse model

of isoproterenol-induced cardiac injury (Wang et al. 2013). Sheng-Mai-San has also been shown

to reduce infarct size in rabbits when administered up to three days prior to infarction, with no

benefit observed with acute treatment (Wang et al. 2001). The benefit was proposed to be

mediated by activation of protein kinase C and opening of mitochondrial ATP-sensitive

potassium channels primarily attributable to the presence of ginsenosides and lignans as the

primary active ingredients in this formulation (Wang et al. 2001). Zhao et al. (2016) have

reported that a Sheng-mai-san derived product, YiXin-Shu, specifically developed for the

treatment of ischemic heart disease, attenuates myocardial ischemic and reperfusion injury in

hypercholesterolemic mice through a mechanism involving inhibition of myocardial apoptosis by

blunting mitochondrial mediated pro-apoptosis pathways, reduction in oxidative stress as well as

by upregulating the nuclear LXRα receptor.

Administering the herbal preparation Danshen, containing notoginseng has also been shown to

exert numerous protective effects in rats subjected to acute coronary artery ligation and

reperfusion (Ren-an et al. 2014). As for several other ginseng-related products this protection

was associated with activation of the Akt myocardial salvage pathway (Ren-an et al. 2014).

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Clinical evidence for cardioprotection

As is the case for most areas of ginseng research related to cardiovascular therapeutics, there is a

paucity of strong translational evidence demonstrating clinical benefit. In the case of

cardioprotection there is some evidence for benefit seen in patients undergoing reperfusion with

either thrombolytic therapy (Guo and Zhang 2001) or percutaneous coronary intervention

(PCI/angioplasty) (Geng et al. 2004) as demonstrated by reduced injury and improved function

in those patients receiving Shenmai. In fact, a meta-analysis of clinical studies in which Shenmai

was administered to patients following myocardial infarction showed some benefit in terms of

reduced mortality, development of heart failure, circulatory shock and re-infarction (Hu et al.

2012). However, as pointed out by the authors themselves these analyses have serious

limitations in view of the small sample size in individual trials and thus should be interpreted

cautiously (Hu et al. 2012). In a small study, patients undergoing PCI and receiving Traditional

Chinese Medicine consisting of P quinquefolius plus Salviae miltiorrhizae in addition to standard

medical treatment demonstrated improved left ventricular function compared to standard

treatment alone (Qiu et al. 2009). A substantially larger clinical trial has been initiated in

December 2014 in China to determine the potential benefit of P quinquefolius in addition to

standard medical treatment in patients who have undergone PCI. This multicenter, placebo-

controlled, double-blind, randomized controlled clinical trial consisting of 1100 patients

administered Xinyue capsules whose major component is P quinquefolius saponins or placebo

capsules for twenty-four weeks (Guo et al. 2016). At time of writing, no results from this trial

have as yet been reported

Ahn et al. (2011) reported beneficial effects of Korean red ginseng in patients who have suffered

an acute myocardial infarction and who were administered the ginseng extract following

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coronary stenting. These patients demonstrated improved coronary reserve eight months after

treatment which was associated with increased levels of pro-angiogenic cells as well as reduced

inflammation, thus demonstrating an overall cardioprotective effect (Ahn et al. 2011).

Conclusion and future directions

There is a substantial amount of unequivocal experimental data supporting the concept of a

cardioprotective effect of ginseng and ginseng-containing products (summarized in Table 2). As

is the case for many naturally-derived products and ginseng in particular, robust clinical evidence

for the use of ginseng products for protecting the ischemic myocardium is generally lacking in

view of the absence for large scale and well-designed, randomized and placebo-controlled Phase

3 clinical trials. Although challenging to establish for a variety of reasons, such clinical

evaluations are necessary in order to bring ginseng into the widespread clinical arena for cardiac

protection. Unfortunately, the history of translational success of cardioprotective strategies first

shown to be effective in animal studies has been most disappointing (Bolli et al. 2004; Lefer and

Marban 2017). Clearly, substantial work is required in this area in order to fulfil the promise of

ginseng as an effective therapy for the protection of the jeopardized myocardium. In view of the

poor outcomes from cardioprotection clinical studies using single medications it is likely that any

benefit from ginseng will likely be seen when used in combination with other medications and

indeed, various examples of superior efficacy with combinatiom therapy have been cited in this

review. However, this polypharmacy approach does present a challenge particularly in the area

of potential drug interactions which has not been extensively studied vis-à-vis ginseng and

commonly used prescription pharmacological agents. Yet interactions between various drugs and

herbal medications including ginseng have been reported, particularly in older individuals

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(Agbabiaka et al. 2017). Thus, this represents an important area which needs to be explored in

greater detail.

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Acknowledgements

Work from the authors’ laboratory was supported by the Canadian Institutes of Health Research

and the Ontario Ginseng Innovation and Research Consortium. Professor Karmazyn is a former

Canada Research Chair in Experimental Cardiology (2004-2016).

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Figure 1. Cascade of events leading to either reversible or irreversible myocardial ischemia

after reperfusion. Note that when performed early, reperfusion can lead to myocardial recovery.

However, when prolonged further intracellular cellular changes including generation of reactive

oxygen species (ROS), elevations in intracellular Ca2+

levels and mitochondrial remodelling can

lead to cell death via apoptosis or other processes. NHE-1; sodium-hydrogen exchange isoform

1; NCX; sodium-calcium exchange; mPTP; mitochondrial permeability transition pore.

Figure 2. Simplified diagram showing how ginsenoside-induced activation of the

phosphoinositide 3-kinase (PI3K) Akt/PKB pathway via receptor tyrosine kinase (RTK)

stimulation can lead to the generation of nitric oxide (NO) resulting in cardiac protection

secondary to upregulation of endothelial nitric oxide synthase (eNOS). Please refer to text for

details.

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Table 1. Examples of some cardioprotective strategies in animal/experimental models

______________________________________________________________________________

Intervention Selected references

Calcium channel blockers Gaviraghi et al. 1995

Sodium-hydrogen exchange inhibitors Karmazyn 2013

Antioxidants/free radical scavengers Becker 2004

Eicosanoids (eg prostacyclin) Szekeres et al. 1991

Ischemic preconditioning Stokfisz et al. 2017

Ischemic postconditioning Heusch 2015

Adenosine receptor activation Donato and Gelpi 2003

Glucose-insulin-potassium solution LaDisa et al. 2004

ATP-sensitive K+ channel activation Testai et al. 2007

Nitrates/nitrites Bryan et al. 2007

Nitric oxide Bice et al. 2016

Neutrophil inhibitors/depletion Werns and Lucchesi 1988

Opioid receptor agonists Peart et al. 2005

P2Y receptor activation Djerada et al. 2017

RISK* pathway activation Hausenloy and Yellon 2007

Stress (heat shock) protein induction Currie et al. 1988

Gene therapy Lavu et al. 2011

Stem cell therapy Yu et al. 2017

Inhibition of microRNAs Kukreja et al. 2011

______________________________________________________________________________

*Reperfusion Injury Salvage Kinase

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Table 2. Experimental evidence for cardioprotective effects of ginseng, ginsenosides and ginseng-related products in various experimental

models

_____________________________________________________________________________________________________________________

Experimental model Treatment Primary effects Primary mechanism Reference

______________________________________________________________________________________________________________________

Isolated IR rat heart Trilinolein Mitochondrial protection Antioxidant,↑MF, ↓Ca2+ Chan et al.

1996, 1997

P ginseng ↓injury Antioxidant Kim and Lee,

2010

Ginsenoside Rb1 ↓injury ↓succinate accumulation, ↑PDH ac3vity Li et al., 2017

ROS treated myocytes P quinquefolius ↓cell death Antioxidant Shao et al.,

2004;

Mehendale et

al., 2005

H2O2 treated myocytes Ginsenoside Re ↓cell death Antioxidant Xie et al., 2006

P quinquefolius ↓cell death Antioxidant Xu et al., 2013

HR myocytes Ginsenoside Rb1 ↓apoptosis ↓succinate accumula3on, ↑PDH ac3vity Li et al., 2017

Ginsenoside Rg1 ↓cell death Antioxidant, ↓Ca2+ Zhu et al. 2009

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Ginsenoside Rg5 ↓apoptosis ↓mitochondrial damage Yang et al.,

2017

Shenfu ↓cell death ↓apoptosis Wang et al.

2009

TG treated myocytes P quinquefolius ↓cell death ↓ER stress Liu et al., 2015

Canine AMI P quinquefolius ↓infarct size Antioxidant Sui et al. 2001

Rat AMI EPC ↓oxida3ve injury Antioxidant, ↓ER stress Xue et al., 2013

EPC ↓infarct size Antiplatelet, anticoagulation Xue et al., 2015

P quinquefolius ↓infarct size, ↑LV func3on ↓ER stress, ↓apoptosis Liu et al. 2013

P quinquefolius ↓infarct size Antioxidant Wang et al.,

2009; Xu et al.,

2013

P quinquefolius ↓apoptosis ↑Bcl-2, ↓Fas protein Yin et al., 2005

P quinquefolius ↑micro vessel density ↑angiogenesis Wang et al.,

2007

Xuesaitong ↓infarct size Numerous protein targets Wang et al.,

2013

P notoginseng ↓infarct size C-kit+ BMSC mobilization Zhang et al.,

2011

P notoginseng ↓infarct size ↓oxida3ve stress, ↓inflamma3on Han et al., 2013

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P notoginseng ↓apoptosis ↑angiogenesis Yang et al.,

2016

P ginseng ↓infarct size ↑ PI3K- Akt- eNOS activity (ARD) Pei et al., 2013

Ginsenoside Rg1 ↑LV func3on Not determined Deng et al.,

2015

P japonicas ↓infarct size, ↑ LV func3on Antioxidant, anti-inflammatory, ↓MAPK He et al., 2012;

Wei et al., 2014

Rat pituitrin AMI PNS-HLV ↓infarct size Antioxidant Zhang et al.,

2012

Mouse AMI P ginseng ↓infarct size, ↓arrhythmias ↑ PI3K- Akt- eNOS activity (GR/ER-D) Zhou et al.,

2011

Porcine MI EPC ↓infarct size ↓apoptosis, ↓ER stress Zhu et al., 2013

Rat IR Notoginsenosides ↓infarct size ↑cardioprotec3ve proteins Yue et al., 2012

P quinquefolius ↓apoptosis ↓mPTP opening Li et al., 2014a

Ginsenoside Rb1 ↓infarct size ↑ PI3K- Akt- eNOS activity Wang et al.,

2008

↓infarct size ↓RhoA ac3va3on Cui et al., 2017

Ginsenoside Rb3 ↓infarct size Antioxidant Shi et al., 2011

Ginsenoside Rg1 ↓infarct size ↓RhoA ac3va3on Li et al., 2018

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Shenfu ↓infarct size Antioxidant Zheng et al.,

2004

Danshen ↓infarct size ↓apoptosis, ↑Akt-eNOS pathway Ren-an et al.,

2014

Diabetic rat IR Ginsenoside Rb1 ↓infarct size ↑ PI3K- Akt- eNOS activity Wu et al., 2011;

Xia et al., 2011

Aged rats IR P ginseng ↓infarct size, ↑LV func3on ↑Akt/eNOS, Sirt1 and Sirt3, ↓Erk/caspase 7 Luo et al., 2015

Guinea pig IR Korean red ginseng ↑func3on Antioxidant, anti-inflammatory Aravinthan et

al., 2015

Rabbit IR Shreng-mai-san ↓infarct size ↑PKC, ↑mKATP Wang et al.,

2001

Mouse IR Compound K ↓infarct size ↑Akt-eNOS pathway Tsutsumi et al.,

2011

Rat Iso treatment Korean red ginseng ↓injury, ↑LV func3on Antioxidant Lim et al., 2013

Porcine Iso treatment Korean red ginseng ↓injury, ↑LV func3on Antioxidant Lim et al., 2014

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Mouse Iso treatment Sheng-mai-san ↓injury Antioxidant Wang et al.,

2013

______________________________________________________________________________________________________________________

AMI, acute myocardial infarction; ROS, reactive oxygen species; MF, membrane fluidity; TG, thapsigargin; ER, endoplasmic reticulum; IR,

ischemia + reperfusion; EPC, Panax quinquefolius + Corydalis tuber (also known as Shenyuan); LV, left ventricle; BMSC, bone mesenchymal stem

cells; ARD, androgen receptor dependent; GR/ER-D, glucocorticoid and/or estrogenreceptor-dependent; Iso, isoproterenol; mPTP, mitochondrial

permeability transition pore; PDH, pyruvate dehydrogenase; PNS-HLV, Panax notoginsenoside-loaded core-shell hybrid liposomal vesicles; PKC,

protein kinase C; mKATP, mitochondrial ATP-sensitive potassium channels

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Intracellular acidosis

1031191

Myocardial ischemia

NHE-1 activation

Reverse-mode NCX activation

Increased intracellular Ca2+

mPTP opening

Release of pro-apoptotic and pro-necrotic

factors from mitochondria

CELL DEATH

Reperfusion

RECOVERY

REPERFUSION INJURY(ROS, Ca2+)

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Cell membrane

Extracellular

Intracellular

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Canadian Journal of Physiology and Pharmacology · Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp-2018-0192.R1 Manuscript Type: Review Date Submitted