Pum2 Mediates Sirt1 mRNA Decay and Exacerbates hypoxia/reoxygenation-induced Cardiomyocyte Apoptosis

Pum2 is a ribonucleic acid binding protein that controls target mRNA turnover. It has been reported to be potentially associated with cardiac fibrosis. However, little is known about the role of Pum2 in cardiac disease. In this study, we found that Pum2 was upregulated in the rat heart tissue subjected to ischemia/reperfusion procedure and cultured neonatal rat ventricular cardiomyocytes (NRVMs) with hypoxia/reoxygenation (H/R) treatment. Further, knockdown of Pum2 showed a beneficial effect on H/R treated NRVMs through decreasing caspase 3-associated apoptosis, whereas overexpression of Pum2 increased H/R-induced NRVMs apoptosis. Moreover, our results demonstrated that Sirt1 was identified as the target of Pum2-mediated mRNA decay in cardiomyocytes, and two Pum2 binding elements were found in the 3'-untranslated region of Sirt1 mRNA. Additionally, overexpression of Pum2 prompted the acetylation of LKB1 by decreasing Sirt1's mRNA level, which in turn repressed the activity of AMPK pathway in both normoxic and H/R-treated NRVMs. Finally, our data indicated that the pro-apoptotic effect of Pum2 was dependent on Sirt1 and AMPK. Collectively, our results provide the evidence that Pum2-mediated Sirt1 mRNA decay plays a detrimental role in H/R-induced cardiomyocytes injury.

Keywords: AMPK; Hypoxia/reoxygenation; Pum2; Sirt1; mRNA turnover.