Inhibition of Myocardial Remodeling and Heart Failure by Traditional Herbal Medications: Evidence from Ginseng and ginkgo biloba

Herbal-based medications have been used as therapeutic agents for thousands of years, particularly in Asian cultures. It is now well established that these herbal medications contain potent bioactive phytochemicals which exert a plethora of beneficial effects such as those seen on the cardiovascular system. Among the most widely studied of these herbal agents is ginseng, a member of the genus Panax, which has been shown to produce beneficial effects in terms of reducing cardiac pathology, at least in experimental studies. The beneficial effects of ginseng observed in such studies are likely attributable to their constituent ginsenosides, which are steroid-like saponins of which there are at least 100 and which vary according to ginseng species. Many ginseng species such as Panax ginseng (also known as Asian ginseng) and P quinquefolius (North American ginseng) as well as specific ginsenosides have been shown to attenuate hypertrophy as well as other indices of myocardial remodeling in a wide variety of experimental models. Ginkgo biloba on the other hand has been much less studied although the leaf extract of the ancient ginkgo tree has similarly consistently been shown to produce anti-remodeling effects. Ginkgo’s primary bioactive constituents are thought to be terpene trilactones called ginkgolides, of which there are currently seven known types. Ginkgo and ginkgolides have also been shown to produce anti-remodeling effects as have been shown for ginseng in a variety of experimental models, in some cases via similar mechanisms. Although a common single mechanism for the salutary effects of these compounds is unlikely, there are a number of examples of shared effects including antioxidant and antiapoptotic effects as well as inhibition of pro-hypertrophic intracellular signaling such as that involving the calcineurin pathway which results in the upregulation of pro-hypertrophic genes. Robust clinical evidence represented by large scale phase 3 trials is lacking although there is limited supporting evidence from small trials at least with respect to ginseng. Taken together, both ginseng and ginkgo as well as their bioactive components offer potential as adjuvant therapy for the treatment of myocardial remodeling and heart failure

Cardiomyocyte Antihypertrophic Effect of Adipose Tissue Conditioned Medium from Rats and Its Abrogation by Obesity is Mediated by the Leptin to Adiponectin Ratio.

White adipocytes are known to function as endocrine organs by secreting a plethora of bioactive adipokines which can regulate cardiac function including the development of hypertrophy. We determined whether adipose tissue conditioned medium (ATCM) generated from the epididymal regions of normal rats can affect the hypertrophic response of cultured rat ventricular myocytes to endothelin-1 (ET-1) administration. Myocytes were treated with ET-1 (10 nM) for 24 hours in the absence or presence of increasing ATCM concentrations. ATCM supressed the hypertrophic response to ET-1 in a concentration-dependent manner, an effect enhanced by the leptin receptor antagonist and attenuated by an antibody against the adiponectin AdipoR1 receptor. Antihypertrophic effects were also observed with ATCM generated from perirenal-derived adipose tissue. However, this effect was absent in ATCM from adipose tissue harvested from corpulent JCR:LA-cp rats. Detailed analyses of adipokine content in ATCM from normal and corpulent rats revealed no differences in the majority of products assayed, although a significant increase in leptin concentrations concomitant with decreased adiponectin levels was observed, resulting in a 11 fold increase in the leptin to adiponectin ratio in ATCM from JCR:LA-cp. The antihypertrophic effect of ATCM was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), an effect abrogated by the AdipoR1 antibody. Moreover, the antihypertrophic effect of ATCM was mimicked by an AMPK activator. There was no effect of ET-1 on mitogen-activated protein kinase (MAPK) activities 24 hour after its addition either in the presence or absence of ATCM. Our study suggests that adipose tissue from healthy subjects exerts antihypertrophic effects via an adiponectin-dependent pathway which is impaired in obesity, most likely due to adipocyte remodelling resulting in enhanced leptin and reduced adiponectin levels

North American ginseng (P. quinquefolius) suppresses β adrenergic-dependent signalling, hypertrophy and cardiac dysfunction

There is increasing evidence for a beneficial effect of ginseng on cardiac pathology. Here we determined whether North American ginseng can modulate the deleterious effects of the β-adrenoceptor agonist isoproterenol on cardiac hypertrophy and function using in vitro and in vivo approaches. Isoproterenol was administered for 2 weeks at either 25 mg/kg/day or 50 mg/kg/day (ISO25 or ISO50) via a subcutaneously implanted osmotic mini-pump to either control rats or those receiving ginseng (0.9 g/L in the drinking water ad libitum). Isoproterenol produced time- and dose-dependent left ventricular dysfunction although these effects were attenuated by ginseng. Improved cardiac functions were associated with reduced heart weights as well as prevention in the upregulation of the hypertrophy-related fetal gene expression. Lung weights were similarly attenuated suggesting reduced pulmonary congestion. In in vitro studies, ginseng (10 Οg/ml) completely suppressed the hypertrophic response to 1 ΟM isoproterenol in terms of myocyte surface area as well as reduction in the upregulation of fetal gene expression. These effects were associated with attenuation in both protein kinase A and cAMP response element-binding protein phosphorylation. Ginseng attenuates adverse cardiac adrenergic responses and may therefore be an effective therapy to reduce hypertrophy and heart failure associated with excessive catecholamine production.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Effect of increasing perirenal adipose conditioned medium (ATCM) concentrations on ET-1-induced hypertrophy as determined by cell surface area (A),expression of α-skeletal actin (B) or expression of ANP (C).

<p>Data are expressed as mean + SEM; n = 6–10. *<i>P</i> < .05 from untreated group; ^#<i>P</i> < .05 from ET-1 alone.</p

Postulated mechanisms underlying opposite effects of ATCM from lean and corpulent animals on the hypertrophic response in cardiomyocytes (CM).

<p>ATCM from lean animals secrete copious quantities of adiponectin (ADPN) which activates the AdipoR1 receptor and blocks the hypertrophic response, possibly via increased AMPK phosphorylation (P-AMPK). This condition favours the production of adiponectin in relation to leptin (Lep) which also allows adiponectin to block the prohypertrophic effect of leptin. Although the concentration of adiponectin in ATCM is substantially higher under all conditions when compared to leptin, the ratio of leptin to adiponectin increases dramatically under obesity as reflected by increased leptin release (LEP) concomitant with decreased adiponectin (Adpn). This change in the adiponectin to leptin relationship results in a diminished antihypertrophic effect of adiponectin since its effects can be countered by leptin. At the same time the increased levels of leptin, coupled with decreased adiponectin allows potentially for a direct prohypertrophic effect of leptin acting via its receptor (OBR). As illustrated at the bottom of each panel, the ratio of leptin to adiponectin will dictate the overall hypertrophic response, even though the absolute levels of adiponectin remain substantially higher.</p

Adipokine content in ATCM derived from adipocytes from lean and JCR:LA-cp rats.

<p>Data in panels A to F are grouped based on concentration range whereas values for leptin (G), adiponectin (H) and the leptin to adiponectin ratios (I) for both animal groups are shown separately. Values indicate mean + SEM (n = 6). <i>*P <</i> .05 from lean group.</p

Effect of increasing epididymal adipose conditioned medium(ATCM) concentrations on ET-1-induced hypertrophy as determined by cell surface area (A), expression of α-skeletal actin (B) or expression of ANP (C).

<p>Data are expressed as mean + SEM; n = 6–10. *<i>P</i> < .05 from untreated group; ^#<i>P</i> < .05 from ET-1 alone.</p

Effect of fractionated ATCM using 30 kDa cut-off filters.

<p>Panel A shows surface area for myocytes treated with ET-1 with or without high molecular weight (>30 kDa) or low molecular weight (<30 kDa) ATCM for 24 hours after ET-1 addition whereas B and C show fetal gene α-Skeletal actin and ANP expression, respectively with identical treatments. Values indicate mean + SEM (n = 6). <i>*P <</i> .05 from untreated group; ^<i>#</i><i>P<</i>0.05 from ET-1 alone; ^<i>¥</i><i>P<</i>0.05 from ET-1 + >30kDa ATCM.</p

Comparison between the ability of ATCM derived from adipocytes from lean rats versus ATCM from corpulent JCR:LA-cp rats to inhibit the hypertrophic effect of ET-1.

<p>Panels A to C show hypertrophic responses to ET-1 under various experimental conditions in terms of cell surface area (A), α-Skeletal actin (B) and ANP (C) expression. Note the inability of ATCM from JCR:LA-cp rats to produce any inhibition of ET-1-induced hypertrophy even with the lowest ATCM dilution. Panels D and E show representative micrographs of adipocytes from the two animal groups and corresponding values for adipocyte area, respectively. Values indicate mean + SEM (n = 6). <i>*P <</i> .05 from untreated group; ^#<i>P <</i> .05 from ET-1 alone group. DF, dilution factor.</p