Loss of miR-146a induces cardiomyocyte proliferation after myocardial infarction through targeting Kctd15.

Abstract

Accumulating evidence strongly confirms that microRNAs (miRNAs) play a pivotal role in the development and progression of cardiovascular diseases. Specifically, miR-146a has been demonstrated to be implicated in the pathogenesis of multiple cardiac diseases. Nevertheless, the role of miR-146a in ischemic heart disease and its underlying molecular mechanism remains unclear. The expression levels of miR-146a during different stages of cardiac development were detected by quantitative polymerase chain reaction (qPCR). Gain-of-function and loss-of-function assays were conducted to evaluate the impact of miR-146a on cardiomyocyte (CM) proliferation. A myocardial infarction (MI) model was established, and M-mode echocardiography and Masson's trichrome staining were used to further investigate the effects of miR-146a on cardiac function recovery post-MI. Then, bioinformatics approaches, including RNA-seq, were utilized to predict Kctd15 as a potential target gene of miR-146a. Finally, a dual luciferase reporter assay and rescue experiment were used to verify miR-146a interactions with Kctd15. First, we found that miR-146a expression decreased with age. Then, overexpression of miR-146a inhibited CM proliferation, while miR-146a inhibition promoted CM proliferation in vitro. Similarly, overexpression of miR-146a was impaired in cardiac function recovery post-MI, whereas miR-146a deficiency improved post-MI cardiac function. Further, bioinformatics analysis suggested that miR-146a might regulate CM proliferation by targeting Kctd15, which was confirmed by overexpression of Kctd15 blocking the effect of miR-146a on CM proliferation. The current study demonstrates that miR-146a regulates CM proliferation through the miR-146a/Kctd15 mRNA/Kctd15 protein pathway, which may provide a potential molecular target for preventing and treating myocardial injury. KEY MESSAGES: Acute myocardial infarction (AMI) accounts for about 7 million deaths per year worldwide; the existing treatment methods such as thrombolysis and percutaneous coronary interventions cannot achieve a good prognosis. This study demonstrates that miR-146a is a negative regulator of CM proliferation and exerts its function through Kctd15. Kctd15 was first proposed to be related to CM proliferation. The study provides new support for endogenous CM proliferation and treatment in other cardiovascular diseases.