Abstract
Excessive reactive oxygen species (ROS) plays an important role in myocardial ischemia/reperfusion (I/R) injury, which triggers not only myocardial cellular apoptosis but also autophagy-related cell death, in which volume-sensitive outwardly rectifying (VSOR) Cl− channel-activated by ROS contributes to cell apoptotic volume decrease, playing an incipient incident of cellular apoptosis. However, whether VSOR Cl− channel concurrently participates in autophagy-related cell death regulation remains unclear. To illuminate the issue, studies underwent in myocardial vitro and vivo I/R model. Rats were performed to ischemia 30 minutes and subsequent reperfusion 24-96 hours, ROS scavenger (NAC), VSOR Cl− channel blocker (DCPIB) and autophagy inhibitor (3MA) were administered respectively. Results showed that oxidative stress, LC3-II stain and inflammation in myocardial tissue were markedly increased, lysosome associated membrane protein-2 (LAMP2) were significantly reduced with I/R group as compared with sham group, reperfusion significantly led to damage in myocardial tissue and heart function, whereas the disorder could be rescued through these agents. Moreover, primary neonatal rat cardiomyocytes hypoxia/reoxygenation model were administered, results showed that VSOR Cl− channel-activated by reoxygenation could cause both cell volume decrease and intracellular acidification, which further increased LC3 and depleted of LAMP2, resulting in autophagy-related cell death. Interestingly, VSOR Cl− channel-blocked by DCPIB could stably maintain the cell volume, intracellular pH, abundant LAMP2 and autophagic intensity regardless of ROS intension derived from reoxygenation injury or adding H2O2. These results first demonstrate that VSOR Cl− channel-activated is a pivotal event to trigger autophagy-related death, which reveals a novel therapeutic target to decrease myocardial I/R injury.
Highlights
Myocardial infarction is the leading cause of death worldwide and continues to rise, early restoration of coronary blood flow plays an important role in minimizing myocardial tissue injury through thrombolytic therapy, coronary artery bypass grafting or primary percutaneous intervention [1, 2]
To explore whether volume-sensitive outwardly rectifying (VSOR) Cl- channel-activated by reactive oxygen species (ROS) production was relevant to autophagic cell death in myocardial ischemia/ reperfusion (I/R) injury, the I/R injury model was administered by occluding the left anterior descending coronary artery (LAD) as our described previously [36]
SD rat hearts were subjected to ischemia(30min) followed by reperfusion (24h), ROS scavenger (N-acetyll-cysteine, NAC), blocker of VSOR Cl- channel (DCPIB) and inhibitor of autophagy (3-Methyladenine, 3-MA) were injected intraperitoneally 10 min before reperfusion respectively
Summary
Myocardial infarction is the leading cause of death worldwide and continues to rise, early restoration of coronary blood flow plays an important role in minimizing myocardial tissue injury through thrombolytic therapy, coronary artery bypass grafting or primary percutaneous intervention [1, 2]. Reperfusion may contribute to newer myocardial injury called as myocardial ischemia/ reperfusion (I/R) injury, in which oxidative damage plays a critical role to initiate excess reactive oxygen species (ROS) generation and eventually progresses to cell necrotic, apoptotic and autophagic cell death [35]. Autophagy-induced by various stresses has been gradually determined, any barriers in the autophagic process are likely to lead to dysfunction of mitochondrial autophagy, for instance suppression of constitutive cardiomyocyte autophagy, or impairment of late stages of autophagy in the absence of lysosome associated membrane protein-2 (LAMP2) in patients with Danon disease and in mice with LAMP-2 ablation, resulting in cardiomyopathy. According to current view, reperfusion injury is derived from LAMP-2 depletion, we should focus on impaired autophagosome clearance, which may trigger excessive ROS, causes fragmentary autophagy. The autophagic response is closely connected with the dynamic change of ROS in myocardial ischemia/ reperfusion
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