Abstract P052: Mir379 Regulates Klotho-deficiency Induced Cardiomyocytes Apoptosis Through Smur1 Repression

Abstract

Background and Objective: Klotho is an aging-suppressor gene. Klotho gene deficiency impairs heart function leading to heart failure, but the underlying mechanism remains unknown. MicroRNAs are increasingly recognized to play important roles in cardiomyopathy. The objective of this study is to investigate whether Mir379 regulates Klotho deficiency-associated cardiomyocyte apoptosis. Methods and Results: Using inducible Cre-Loxp recombination technology, we first found that kidney-specific deletion of the Klotho gene caused heart failure and reduced survival. Using microRNA sequencing analysis, we found that Mir379 may be an important mediator of Klotho deficiency-associated heart failure. In H9c2 heart cells, we found that Klotho-free medium induced apoptosis and increased Mir379 levels. To test whether Mir379 mediates Klotho deficiency-associated apoptosis, H9c2 cells were transfected with Mir379 inhibitor. Interestingly, Mir379 inhibitor prevented Klotho deficiency-associated H9c2 cell apoptosis. On the other hand, Mir379 mimic itself caused apoptosis in H9c2 cells. Thus, Mir379 may mediate apoptosis in H9C2 cells treated with Klotho-free medium. Using the mRNA-miRNA target interaction assay, we found that Smurf1 mRNA contained the 3-UTR binding site for Mir379. Importantly, Mir379 mimic suppressed Smurf1 expression. Therefore, Smurf1 repression may be involved in Mir379-induced H9c2 cells apoptosis. Conclusion: Mir379 may mediate Klotho deficiency-associated cardiomyocyte apoptosis through repression of Smurf1, which is required for Mir379-induced apoptotic cell death. Mir379 may be a potential therapeutic option for cardiomyocyte apoptosis or heart failure associated with Klotho deficiency.