Resveratrol Treatment of Mice With Pressure-Overload–Induced Heart Failure Improves Diastolic Function and Cardiac Energy Metabolism

Abstract

Background— Although resveratrol has multiple beneficial cardiovascular effects, whether resveratrol can be used for the treatment and management of heart failure (HF) remains unclear. In the current study, we determined whether resveratrol treatment of mice with established HF could lessen the detrimental phenotype associated with pressure-overload–induced HF and identified physiological and molecular mechanisms contributing to this. Methods and Results— C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks post surgery, a cohort of mice with established HF (% ejection fraction <45) was administered resveratrol (≈320 mg/kg per day). Despite a lack of improvement in ejection fraction, resveratrol treatment significantly increased median survival of mice with HF, lessened cardiac fibrosis, reduced gene expression of several disease markers for hypertrophy and extracellular matrix remodeling that were upregulated in HF, promoted beneficial remodeling, and improved diastolic function. Resveratrol treatment of mice with established HF also restored the levels of mitochondrial oxidative phosphorylation complexes, restored cardiac AMP-activated protein kinase activation, and improved myocardial insulin sensitivity to promote glucose metabolism and significantly improved myocardial energetic status. Finally, noncardiac symptoms of HF, such as peripheral insulin sensitivity, vascular function, and physical activity, were improved with resveratrol treatment. Conclusions— Resveratrol treatment of mice with established HF lessens the severity of the HF phenotype by lessening cardiac fibrosis, improving molecular and structural remodeling of the heart, and enhancing diastolic function, vascular function, and energy metabolism.

Inhibition of Cardiomyocytes Hypertrophy by Resveratrol Is Associated with Amelioration of Endoplasmic Reticulum Stress

“…A large body of evidence has shown that Res may help to prevent the development of certain cancers and cardiovascular diseases due to antiviral, antioxidant and anti-inflammatory actions. A recent study showed that Res may attenuate left ventricular hypertrophy via inhibiting NFAT-dependent transcription and suppress heart failure and reverse myocardial remodeling [21,22]. Res treatment may inhibit high blood pressure and attenuate apoptosis of ventricular myocytes and improve ventricular function [23,24].…”

The Future of Heart Failure Diagnosis, Therapy, and Management

“…To the extent that we are approaching an asymptote with addressing neurohormonal activation, these systems are fertile targets, especially if imaging tools such as MRI or positron emission tomography can be used to identify those patient subsets with the most marked changes for early study of targeted therapeutics. 26,27 Disrupting the Successful Stack of Therapies Once the benefit of ACEi was demonstrated in the Studies of Left Ventricular Dysfunction (SOLVD) trial, additional agents have each been stacked on top of previous standard evidencebased therapy. Orthogonal to the stack has been the principle that assessment and correction of fluid retention is a crucial adjunct to all therapies for HF.…”

Resveratrol Attenuated Low Ambient Temperature-Induced Myocardial Hypertrophy via Inhibiting Cardiomyocyte Apoptosis

“…A large body of evidence has shown that Resveratrol has antiviral, antioxidant and anti-inflammatory actions, and may help prevent the development of certain cancers and cardiovascular diseases [19,22]. Resveratrol at a dosage of 146 mg/kg/day in rats may attenuate pathology left ventricular hypertrophy via inhibiting NFAT-dependent transcription [17].…”

“…Resveratrol at a dosage of 146 mg/kg/day in rats may attenuate pathology left ventricular hypertrophy via inhibiting NFAT-dependent transcription [17]. Resveratrol treatment (~320mg/kg/day) also may suppress transverse aortic constriction (TAC)-induced heart failure and reverse myocardial remodeling by restored cardiac AMP-activated protein kinase (AMPK) activation in mice [22]. Resveratrol treatment (~320mg/kg/day in mice) may inhibit high blood pressure (BP) and prevent myocardial hypertrophy through mediating LKB1-AMPK-eNOS signaling axis [16].…”

“…Besides, Resveratrol can protect hearts against cardiovascular diseases. For example, Resveratrol was shown to suppress left ventricular hypertrophy and heart failure [17,22]. Resveratrol treatment also inhibits ischemia/reperfusion injury and ventricular arrhythmias [23].…”