LATS2 Deletion Attenuates Myocardial Ischemia-Reperfusion Injury by Promoting Mitochondrial Biogenesis.

Yi Chen,Chen Liu,Runzhen Chen,Xiaoxiao Zhao,Hongbing Yan,Peng Zhou,Hanjun Zhao,Jiannan Li,Li Song,Jin Wang

doi:10.1155/2021/1058872

Abstract

Reperfusion therapy is the most effective treatment for acute myocardial infarction, but it can damage cardiomyocytes through a mechanism known as myocardial ischemia/reperfusion injury (MIRI). In this study, we investigated whether the large tumor suppressor kinase 2 (LATS2) contributes to the development of myocardial MIRI by disrupting mitochondrial biogenesis. Our in vitro data demonstrate that cardiomyocyte viability was reduced and apoptosis was increased in response to hypoxia/reoxygenation (H/R) injury. However, suppression of LATS2 by shRNA sustained cardiomyocyte viability by maintaining mitochondrial function. Compared to H/R-treated control cardiomyocytes, cardiomyocytes transfected with LATS2 shRNA exhibited increased mitochondrial respiration, improved mitochondrial ATP generation, and more stable mitochondrial membrane potential. LATS2 suppression increased cardiomyocyte viability and mitochondrial biogenesis in a manner dependent on PGC1α, a key regulator of mitochondrial metabolism. These results identify LATS2 as a new inducer of mitochondrial damage and myocardial MIRI and suggest that approaches targeting LATS2 or mitochondrial biogenesis may be beneficial in the clinical management of cardiac MIRI.

Highlights

Cardiovascular diseases are the leading cause of death worldwide, especially in developing countries [1]
Cultured H9c2 cardiomyocytes were divided into four groups: (1) control group (CONT), (2) H/R injury group (H/R): hypoxia for 2 h followed by reoxygenation for 2 h, and (3) large tumor suppressor kinase 2 (LATS2) transfection group: cells were infected with LATS2 shRNA adenovirus followed by H/R injury [19, 20]
To analyze whether the increased LATS2 expression mediates the H/R-induced cardiomyocyte damage, we measured cell viability in H9C2 cardiomyocytes transfected with LATS2-adenovirus shRNA

Summary

Introduction

Cardiovascular diseases are the leading cause of death worldwide, especially in developing countries [1]. Acute myocardial infarction (AMI) is a major cause of mortality in cardiovascular diseases. For patients with AMI, a rapid and effective opening of the culprit vessel can rescue ischemic myocardium, reduce infarct size, and improve treatment effects [2, 3]. Reperfusion therapy, including thrombolysis, is the most effective treatment for AMI. Reperfusion of blood flow brought about by the opening of a culprit vessel can cause damage to cardiomyocytes, known as myocardial ischemia/reperfusion injury (MIRI). Studies have found that about 50% of myocardial necrosis cases are caused by MIRI [4,5,6].

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Results

Conclusion