Resveratrol, an activator of SIRT1, upregulates AMPK and improves cardiac function in heart failure

Abstract

ABSTRACT. Reduced AMP-activated protein kinase (AMPK) expression has been shown to play a significant role in the cardiac dysfunction in heart failure. This study was designed to examine the effect of resveratrol, a potent activator of silent information regulator (SIRT1), on cardiac function and AMPK expression in heart failure. Adult male rat left anterior descending arteries were ligated, and they were fed with either a regular diet or a diet enriched with resveratrol. Heart failure was produced by myocardial infarction, and was associated with markedly increased AMPK and SIRT1 protein levels. Resveratrol treatment had a tremendous beneficial effect, both in terms of improving AMPK expression and on cardiac function. Decreased cardiac function and AMPK expression were also found in SIRT1 knockout (+/-) mice. In cultured cardiomyocytes, resveratrol increased AMPK and SIRT1 expressions, and overexpression of SIRT1 was found to be sufficient to activate AMPK in H9c2 cells. In contrast, pretreatment of cardiomyocytes with an SIRT1 antagonist, nicotinamide, blocked these beneficial effects of resveratrol. Therefore, the protective effects of resveratrol were found to be dependent on its ability to activate SIRT1 and improve AMPK expression. These results demonstrated that in heart failure, the enzymatic activity of cardiac SIRT1 is increased, which contributes to increased expression of AMPK, and resveratrol enhances the expression of AMPK and improves cardiac function through the activation of SIRT1.

Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases

“…In addition, Xuan et al performed left coronary artery ligation on mice and found that resveratrol (20 mg/kg/day for 42 days) decreased cardiac remodeling and increased survival following the MI [168]. Similar positive results were observed in rats treated with 2.5 mg/kg/day resveratrol for 16 weeks post-MI [169]. In this latter study, resveratrol treated rats had improved cardiac function, decreased mortality, and decreased B-type natriuretic peptide (BNP) serum levels, demonstrating that resveratrol protected against the development of MI-induced heart failure [170].…”

“…In addition to the role of AMPK, SIRT1 has been implicated in the ability of resveratrol to promote autophagy. For instance, in a MI model in rats, resveratrol increased SIRT1 and AMPK expression, and in vitro studies indicated that inhibition of SIRT1 decreased AMPK levels [169]. Moreover, in mice pretreated with resveratrol, a decrease in infarct size coupled with an increase in deacetylated substrate (indicating SIRT1 activation) was observed following ischemia-reperfusion [164].…”

SIRT1 regulates autophagy and diploidization in parthenogenetic haploid embryonic stem cells

“…As known, the activity of SIRT1 depended on NAD þ and NAM interacted with SIRT1 via binding at the C pocket to feedback inhibit NAD þ [11,12]. Immunofluorescence staining revealed that the SIRT1-knockdown effects of shSIRT1 mostly occurred in the nucleus of ph ESCs, whereas NAM distributed in the cytoplasm (Fig.…”

“…To further investigate the mechanism underlying the regulation of p53 by SIRT1 in ph ESCs, resveratrol (trans-3,4 0 ,5-trihydroxystilbene), was used as a potent activator of SIRT1 through AMP-activated protein kinase (AMPK) induction [11,12]. AMPKa2 was a crucial catalytic subunit from AMPK phosphorylation.…”

Cardiac metabolism — A promising therapeutic target for heart failure

“…To date there are no clinical trials that have studied PPARα agonists as specific metabolic therapies in HF. Activators of the PPAR regulator SIRT-1 however, such as resveratrol (which also activates AMPK by inhibiting ATP synthase; Price, et al, 2012), have been tested in the pre-clinical setting and were found to reduce oxidative stress in failing hamster hearts (Tanno, et al, 2010) and improve cardiac function in rats subjected to arterial ligation (Gu, et al, 2014). It has been identified however, that overexpression of SIRT-1 can impair diastolic function and in fact may cause DCM (Kawashima, et al, 2011).…”