SIRT1 increases cardiomyocyte binucleation in the heart development

// Alexandra N. Shin 1, 2, * , Limin Han 1, * , Chiranjib Dasgupta 1 , Lei Huang 1 , Shumei Yang 3 and Lubo Zhang 1 1 The Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA 2 Department of Biological Sciences, California Baptist University, Riverside, California, USA 3 Department of Chemistry and Biochemistry, California State University, San Bernardino, California, USA * These authors contributed equally to this work Correspondence to: Lubo Zhang, email: lzhang@llu.edu Keywords: binucleation; hypoxia; miR-133a; SIRT1; cardiomyocyte Received: June 01, 2017      Accepted: November 05, 2017      Published: January 03, 2018 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.