Abstract
SIRT1, a mammalian ortholog of yeast silent information regulator 2 (Sir2), is an NAD+-dependent protein deacetylase that plays a critical role in the regulation of vascular function. The current study aims to investigate the functional significance of deacetylase activity of SIRT1 in heart. Here we show that the early postnatal hearts expressed the highest level of SIRT1 deacetylase activity compared to adult and aged hearts. We generated transgenic mice with cardiac-specific expression of a dominant-negative form of the human SIRT1 (SIRT1H363Y), which represses endogenous SIRT1 activity. The transgenic mice displayed dilated atrial and ventricular chambers, and died early in the postnatal period. Pathological, echocardiographic and molecular phenotype confirmed the presence of dilated cardiomyopathy. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling analysis revealed a greater abundance of apoptotic nuclei in the hearts of transgenic mice. Furthermore, we show that cardiomyocyte apoptosis caused by suppression of SIRT1 activity is, at least in part, due to increased p53 acetylation and upregulated Bax expression. These results indicate that dominant negative form of SIRT1 (SIRT1H363Y) overexpression in mouse hearts causes cardiomyocyte apoptosis and early-onset heart failure, suggesting a critical role of SIRT1 in preserving normal cardiac development during the early postnatal period.
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Mu, W., Zhang, Q., Tang, X. et al. Overexpression of a dominant-negative mutant of SIRT1 in mouse heart causes cardiomyocyte apoptosis and early-onset heart failure. Sci. China Life Sci. 57, 915–924 (2014). https://doi.org/10.1007/s11427-014-4687-1
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DOI: https://doi.org/10.1007/s11427-014-4687-1