SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice

Abstract

Background Diabetic cardiomyopathy (DCM) is a major threat for diabetic patients. Silent information regulator 1 (SIRT1) has a regulatory effect on mitochondrial dynamics, which is associated with DCM pathological changes. Our study aims to investigate whether resveratrol, a SRIT1 activator, could exert a protective effect against DCM. Methods and Results Cardiac-specific SIRT1 knockout (SIRT1KO) mice were generated using Cre-loxP system. SIRT1KO mice displayed symptoms of DCM, including cardiac hypertrophy and dysfunction, insulin resistance, and abnormal glucose metabolism. DCM and SIRT1KO hearts showed impaired mitochondrial biogenesis and function, while SIRT1 activation by resveratrol reversed this in DCM mice. High glucose caused increased apoptosis, impaired mitochondrial biogenesis, and function in cardiomyocytes, which was alleviated by resveratrol. SIRT1 deletion by both SIRT1KO and shRNA abolished the beneficial effects of resveratrol. Furthermore, the function of SIRT1 is mediated via the deacetylation effect on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), thus inducing increased expression of nuclear respiratory factor 1 (NRF-1), NRF-2, estrogen-related receptor-α (ERR-α), and mitochondrial transcription factor A (TFAM). Conclusions Cardiac deletion of SIRT1 caused phenotypes resembling DCM. Activation of SIRT1 by resveratrol ameliorated cardiac injuries in DCM through PGC-1α-mediated mitochondrial regulation. Collectively, SIRT1 may serve as a potential therapeutic target for DCM.

Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

“…Decreased SIRT1 expression was found in diabetic hearts while normalizing or activating SIRT1 signaling alleviated diabetes‐induced cardiac dysfunction . It has been reported that activation of SIRT1 improves mitochondrial function and attenuates cardiac dysfunction in diabetic animals . However, whether SIRT1 signaling is involved in the regulatory effect of melatonin on mitochondrial fission is unknown.…”

MiR‐144 protects the heart from hyperglycemia‐induced injury by regulating mitochondrial biogenesis and cardiomyocyte apoptosis

“…Therefore, the crosstalk between AMPK activation and Rac‐1 activity is still not well elucidated. Previous in vivo and in vitro data with hyperglycemic models showed that increased Rac‐1 activity and decreased AMPKα phosphorylation were accompanied by increased PGC‐1α acetylation, which was regulated by acetylation at multiple sites occurring through silent information regulator 1 during fasting and DCM . We therefore speculated that forced Rac‐1 activity may elicit feedback inhibition of AMPK activation and PGC‐1α acetylation.…”

Gnetol, a Resveratrol Derivative Ameliorates Malathion-Induced Neurotoxicity through Modulating Lysosomal Membrane Permeabilization in N2a Cells

“…Resveratrol, a potential activator of SIRT1 inhibits aging disease like AD by mimic caloric restriction in animal models [33]. In diabetic cardiomyopathy and hypertrophy adult rat, resveratrol ameliorates apoptosis, mitochondrial biogenesis, hypertrophy and cardiomyocytes functions by SIRT1 mediated activation of nuclear respiratory factor 1 (NRF-1), NRF-2, AMPK, estrogen-related receptor-α (ERR-α), and mitochondrial transcription factor A (TFAM) [34,35].…”