Oncotarget

Research Papers:

SIRT1 increases cardiomyocyte binucleation in the heart development

Alexandra N Shin _, Limin Han, Chiranjib Dasgupta, Lei Huang, Shumei Yang and Lubo Zhang

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Oncotarget. 2018; 9:7996-8010. https://doi.org/10.18632/oncotarget.23847

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Abstract

Alexandra N. Shin1,2,*, Limin Han1,*, Chiranjib Dasgupta1, Lei Huang1, Shumei Yang3 and Lubo Zhang1

1The Lawrence D. Longo MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA

2Department of Biological Sciences, California Baptist University, Riverside, California, USA

3Department 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.


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