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.

• Authors: Sai Ma, Jing Feng, Ran Zhang, Jiangwei Chen, Dong Han, Xiang Li, Bo Yang, Xiujuan Li, Miaomiao Fan, Congye Li, Zuhong Tian, Yabin Wang, Feng Cao
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2017 Pg. 4602715 ( 2017) ISSN: 1942-0994 [Electronic] United States
• PMID: 28883902 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• Mitochondrial Proteins
• NF-E2-Related Factor 1
• Receptors, Estrogen
• Stilbenes
• Transcription Factors
• mitochondrial transcription factor A
• Sirtuin 1
• Resveratrol

Topics

• Animals
• Cell Line
• DNA-Binding Proteins (metabolism)
• Diabetic Cardiomyopathies (drug therapy, metabolism)
• Humans
• Mice
• Mice, Knockout
• Mice, Transgenic
• Mitochondria (drug effects, metabolism)
• Mitochondrial Proteins (metabolism)
• NF-E2-Related Factor 1 (metabolism)
• Receptors, Estrogen (metabolism)
• Resveratrol
• Sirtuin 1 (metabolism)
• Stilbenes (therapeutic use)
• Transcription Factors (metabolism)
• ERRalpha Estrogen-Related Receptor