Leptin Regulates the Ventricular Remodeling and Mitochondrial Dysfunction through miR-27a/b-3p/Mitochondrial Fission Factor (MFF)/Optic Atrophy 1 (OPA1) Axis

Abstract

Purpose: Leptin was reported to be associated with and is considered a risk factor for acute myocardial infarction (AMI). The aim of this study was to investigate the role and related regulation mechanism of Leptin in the myocardial infarction induced dysfunctions. Methods: MI (myocardial infarction) rat model was established to explore the role of Leptin on myocardial functions. Eighteen rats are divided into three group, including control rat, Leptin rat and MI rat. Echocardiography was performed to check left ventricular function. The hypoxic cell model was established, using H9C2 cardiomyocytes cell, to investigate the related controlling mechanism of Leptin. The miR-27a/b-3p expression in MI-rats was measured via quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The interaction between miR-27a/b-3p and mitochondrial fission factor (MFF) was checked for using double luciferase reporter gene. The glucose consumption and the lactic acid production in hypoxic cell model were utilized to estimate the cellular energy metabolism. Results: Leptin expression was significantly increased and miR-27a/b-3p expression was significantly decreased in MI-rats (p < 0.01). Leptin knockdown significantly alleviated the myocardial dysfunction of MI-rats (p < 0.01). miR-27a/b-3p expression was significantly downregulated in the hypoxic cell model and the cardiomyocytes of MI-rats (p < 0.01). MFF was proved to be a downstream target of miR-27a/b-3p, and its overexpression reversed the influence of miR-27a/b-3p on the lactic acid production and the cellular energy metabolism of the hypoxic cell model. Moreover, miR-27a/b-3p significantly elevated the abundances of mitochondrial proteins optic atrophy (OPA1), mitofusin-1 (MFN1) and mitofusin-2 (MFN2) (p < 0.01), and decreased the levels of proteins hexokinase 2 (HK2), lactate dehydrogenase A (LDHA) and phosphorylated Akt (p-AKT), and MFF upregulation could significantly reverse these phenomena. Conclusions: Leptin participates in ventricular remodeling and the mitophagy of cardiomyocytes, by regulating miR-27a/b-3p/mitochondrial fission factor (MFF)/optic atrophy 1 protein (OPA1) axis.