Abstract
SIRT1 regulates cell senescence. We investigated a novel role of SIRT1 in the regulation of cardiomyocyte terminal differentiation in the developing heart. Retinoic acid (RA)-induced binucleation of H9c2 cells was associated with increased SIRT1 expression. Inhibition of SIRT1 activity or expression significantly decreased RA-induced binucleation. SIRT1 expression was minimal in the fetal heart and significantly upregulated in the hearts of postnatal day 7 (P7) rat pups. In contrast, heart-specific miR-133a expression was high in the fetal heart but significantly reduced in P7 pup hearts. The miR-133a promoter contains a canonical HRE element and hypoxia upregulated miR-133a gene expression in the heart. SIRT1 mRNA 3′UTR has miR-133a binding sequences and miR-133a and hypoxia suppressed SIRT1 expression in cardiomyocytes. Of importance, inhibition of SIRT1 significantly reduced binucleated cardiomyocytes in the hearts of P7 pups. Taken together, the present study reveals a novel role of SIRT1 and its regulation by miR-133a in cardiomyocyte terminal differentiation of the developing heart, and suggests a potential therapeutic strategy that may impact cardiac function later in life.
Highlights
Cardiomyocytes are the functional units of the heart, and undergo terminal differentiation as they mature from fetal to adult hearts [1,2,3,4]
The present study reveals a novel role of sirtuin 1 (SIRT1) and its regulation by miR-133a in cardiomyocyte terminal differentiation of the developing heart, and suggests a potential therapeutic strategy that may impact cardiac function later in life
We provide evidence for a novel role of SIRT1 in the regulation of terminal differentiation and binucleation of cardiomyocytes in the heart development
Summary
Cardiomyocytes are the functional units of the heart, and undergo terminal differentiation as they mature from fetal to adult hearts [1,2,3,4]. This terminal differentiation process occurs around birth, in which the cardiomyocytes exit the cell cycle, become binucleated and lose their ability to proliferate [1, 5,6,7]. Adult cardiomyocytes have lost their proliferative capacity and have negligible increases in number following birth [8]. SIRT1 can be activated through nicotinamide-depletion, whereas nicotinamide (NAM) itself is shown to inhibit SIRT1 activity [24]
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