SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis

Abstract

Heart failure is an aging-associated disease, which is the leading cause of death worldwide. Sirtuin family members have been largely studied in the context of aging and agingassociated diseases. Sirtuin 2 (SIRT2) is a cytoplasmic protein in the family of sirtuins that are NAD + -dependent class III histone deacetylases. In this work, we studied the role of SIRT2 in regulating NFAT transcription factor and the development of cardiac hypertrophy. Confocal microscopy analysis indicated that SIRT2 is localized in the cytoplasm of cardiomyocytes and SIRT2 levels are reduced during pathological hypertrophy of the heart. SIRT2 deficient mice develops spontaneous pathological cardiac hypertrophy, remodelling, fibrosis and dysfunction in an age-dependent manner. Moreover, young SIRT2 deficient mice develops exacerbated agonist-induced hypertrophy. On contrast, SIRT2 overexpression attenuated agonist-induced cardiac hypertrophy in cardiomyocytes in a cell autonomous manner. Mechanistically, SIRT2 binds to and deacetylates NFATc2 transcription factor. SIRT2 deficiency stabilizes NFATc2 and enhances nuclear localization of NFATc2, resulting in increased transcription activity. Our results suggest that inhibition of NFAT rescues the cardiac dysfunction in SIRT2 deficient mice. Thus, our study establishes SIRT2 as a novel endogenous negative regulator of NFAT transcription factor. _____________________________________

Sirt2-SUMOylation is essential for its tumor-suppressor function in neuroblastoma

“…Considering of this, we compared the half-life of P38 with or without Sirt2 expression, the result conversely showed that deacetylated P38 was more stable than the acetylated one ( Fig. 4G & Fig S3C), which was consistent with a certain phenomenon that Sirt2 de ciency can stabilize NFATc2 to enhance its transcription activity [34].…”

Controversial Impact of Sirtuins in Chronic Non-Transmissible Diseases and Rehabilitation Medicine

“…In fact, during pathological hypertrophy, Sirt2 levels are significantly reduced in the human heart, and this condition has been confirmed by Sirt2 deficient animals in which agonist-induced hypertrophy is exacerbated while Sirt2 overexpression attenuates hypertrophy in cardiomyocytes [67]. In case of Sirt2 reduction, cardiac remodeling apparently occurs in consequence of missing interaction between Sirt2, that cannot migrate into the nucleus in G2/M phase, and the transcription factor NFAT isoform C2 (NFATc2) which is not deacetylated resulting in increased transcription activity of foetal cardiac genes which contribute to hypertrophy [67]. In vitro, the downregulation of Sirt2 in embryonic myoblasts enhances anoxia-reoxygenation stress tolerance sequestering Bad and contrasting the progression of cell death [25].…”

Elevated plasma Sirtuin2 level predicts heart failure after acute myocardial infarction

“…Previous studies demonstrated that SIRT2 is a protective factor in cardiovascular disease and also showed that expression levels of SIRT2 protein were down-regulated in cardiomyocytes treated with phenylephrine or isoproterenol 7 , as well as in hypertrophic hearts of mice 6 or even in hearts of T1DM rats 22 . Sirt2-KO markedly exaggerated cardiac hypertrophy and brosis, as well as causing decreases of cardiac ejection fraction and fractional shortening in aged mice and Ang II-infused mice 6 ; besides, overexpression of SIRT2 attenuated agonist-induced cardiac hypertrophy in cardiomyocytes 7 . Moreover, SIRT2 mediates hypertension-induced vascular remodeling 23 .…”

“…Recently, SIRT2, as a member of sirtuin family, was reported to play a signi cant role in cardiovascular disease. It has been previously shown that over expression of cardiac-speci c SIRT2, promoting AMP-activated protein kinase (AMPK) activation, can protect heart against Ang II-induced cardiac hypertrophy and brosis 6 , while SIRT2 can repress nuclear factor of activated T-cells (NFAT) to maintain cardiac homeostasis and ameliorate cardiac dysfunction 7 . In addition, SIRT2 gene is down-regulated in the cardiac tissue in cardiosurgical patients undergoing remote ischemic preconditioning 8 , and functional genetic variants in acute myocardial infarction(AMI) patients were observed as well 9 .…”