Autophagy Is Involved in the Cardioprotection Effect of Remote Limb Ischemic Postconditioning on Myocardial Ischemia/Reperfusion Injury in Normal Mice, but Not Diabetic Mice

Zhihua Han,Kan Chen,Zhaofang Yin,Jiatian Cao,Lin Gao,Dongqiang Song,Yue Wang,Lei Tian,Changqian Wang,Yuqi Fan,Rajesh Mohanraj

doi:10.1371/journal.pone.0086838

Abstract

BackgroundRecent animal study and clinical trial data suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection. However, during ischemia reperfusion injury (IR), the effect and mechanism of RIPostC on myocardium in subjects with or without diabetes mellitus (DM) are poorly understood. Autophagy plays a crucial role in alleviating myocardial IR injury. The aim of this study was to determine the effect of RIPostC on mice myocardial IR injury model with or without DM, and investigate the role of autophagy in this process.Methodology and ResultsStreptozocin (STZ) induced DM mice model and myocardial IR model were established. Using a noninvasive technique, RIPostC was induced in normal mice (ND) and DM mice by three cycles of ischemia (5 min) and reperfusion (5 min) in the left hindlimb. In ND group, RIPostC significantly reduced infarct size (32.6±3.0% in ND-RIPostC vs. 50.6±2.4% in ND-IR, p<0.05) and improved cardiac ejection fraction (49.70±3.46% in ND-RIPostC vs. 31.30±3.95% in ND-IR, p<0.05). However, in DM group, no RIPostC mediated cardioprotetion effect was observed. To analyze the role of autophagy, western blot and immunohistochemistry was performed. Our data showed that a decreased sequestosome 1 (SQSTM1/p62) level, an increased Beclin-1 level, and higher ratio of LC3-II/LC3-I were observed in ND RIPostC group, but not DM RIPostC group.ConclusionsThe current study suggested that RIPostC exerts cardioprotection effect on IR in normal mice, but not DM mice, and this difference is via, at least in part, the up-regulation of autophagy.

Highlights

Infarct size is a major determinant of mortality in acute myocardial infarction (AMI), a main cause of death worldwide, especially in the industrial countries
The current study suggested that remote limb ischemic postconditioning (RIPostC) exerts cardioprotection effect on IR in normal mice, but not diabetes mellitus (DM) mice, and this difference is via, at least in part, the up-regulation of autophagy
As autophagy activity was upregulated significantly after 3 hours of postreperfusion, we evaluated the changes of autophagy under the RIPostC at the same time point by western blot analysis, immunohistochemistry assay and transmission electron microscopy (TEM)

Summary

Introduction

Infarct size is a major determinant of mortality in acute myocardial infarction (AMI), a main cause of death worldwide, especially in the industrial countries. The most effective way to limit infarct size is to reopen the ‘‘culprit’’ vessel and reperfuse the jeopardized myocardium with thrombolytic drugs or primary PCI as soon as possible [2]. Zhao et al reported that post ischemic conditioning (three cycles of 30-s reperfusion and 30-s left anterior artery reocclusion) is as effective as preconditioning in reducing infarct size and preserving endothelial function in swine myocardial IR model [3]. Recent animal study and clinical trial data suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection. The aim of this study was to determine the effect of RIPostC on mice myocardial IR injury model with or without DM, and investigate the role of autophagy in this process

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