Abstract
Acute myocardial infarction (MI) is one of the leading causes of death in the world, and its pathophysiological mechanisms have not been fully elucidated. The purpose of this study was to investigate the role and mechanism of uncoupling protein 2 (UCP2) after MI in mouse heart. Here, we examined the expression and role of UCP2 in mouse heart 4 weeks after MI. The expression of UCP2 was detected by RT-PCR and western blotting. Cardiac function, myocardial fibrosis, and cardiomyocyte apoptosis were assessed by echocardiography and immunohistochemistry. Phosphatase dynamin-related protein1 (P-DRP1) and myocardial fibrosis-related proteins were measured. Cardiomyocytes were exposed to hypoxia for 6 h to mimic the model of MI. Mdivi, an inhibitor of P-DRP1, was used to inhibit DRP1-dependent mitochondrial fission. Mitochondrial superoxide, membrane potential, oxygen consumption rate, and cardiomyocyte apoptosis were detected after hypoxia. It is shown mitochondrial superoxide, membrane potential, oxygen consumption rate, and cardiomyocyte apoptosis were dependent on the level of P-DRP1. UCP2 overexpression reduced cardiomyocyte apoptosis (fibrosis), improved cardiac function and inhibit the phosphorylation of DRP1 and the ratio of P-DRP1/DRP1. However, inhibition of DRP1 by mdivi did not further reduce cell apoptosis rate and cardiac function in UCP2 overexpression group. In addition, bioinformatics analysis, luciferase activity, and western blot assay proved UCP2 was a direct target gene of microRNA-762, a up-regulated microRNA after MI. In conclusion, UCP2 plays a protective role after MI and the mechanism is involved in microRNA-762 upstream and DRP1-dependent mitochondrial fission downstream.
Highlights
Acute myocardial infarction (MI) caused by coronary heart disease (CHD) is very common in clinical practice and is associated with high morbidity and mortality [1]
We found the expression of Uncoupling protein 2 (UCP2) is downregulated by miR-762 and UCP2 has a protective role in cardiomyocyte apoptosis and fibrosis, and improve cardiac function after MI
An Annexin V-FITC, Propidium Iodide (PI) Detection Kit,m and A terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) kit were purchased from BD Biosciences (New Jersey, USA); The following primary antibodies were used in this experiment: anti-GAPDH (1:100, Cell Signaling Technology, USA), anti-UCP2 (1:5,000, R&D Systems, Inc, USA), anti-Matrix metallo proteinase 9 (MMP9)
Summary
Acute myocardial infarction (MI) caused by coronary heart disease (CHD) is very common in clinical practice and is associated with high morbidity and mortality [1]. The pathophysiological process of this disease is complex and its mechanisms have not been entirely elucidated [2]. The protective effect of UCP2 on atherosclerosis has been studied, and its mechanism may be related to macrophage metabolism and thermogenesis [8]. The roles of UCP2 in the heart have not yet been fully elucidated. Even in the same disease, UCP2 may play different roles. Concerning CHD, some studies demonstrated that diabetic patients after MI cohort with the UCP2-866A allele have poorer survival [11, 12]. Another study showed the UCP2-866A allele is associated with reduced risk of CHD in type 2 diabetic men in a 6-year prospective study [13]. There is an urgent need to establish the roles of UCP2 in CHD, and this study aims to explore the role of UCP2 in mouse heart after MI
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