Jichun Wang1,2,3, Li Lu1,2,3, Sisi Chen1,2,3, Jing Xie1,2,3, Shuai Lu1,2,3, Yanli Zhou1,2,3, Hong Jiang1,2,3. 1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China. 2. Cardiovascular Research Institute, Wuhan University, Wuhan, China. 3. Hubei Key Laboratory of Cardiology, Wuhan, China.
Abstract
BACKGROUND: Ischemia-reperfusion (I/R) injury, which leads to additionally cardiac tissue damage, is a severe adverse effect of reperfusion therapeutics used for the treatment of acute myocardial infarction. Agents capable of alleviating I/R-induced myocardial injury are urgently needed. In this study, we investigated whether up-regulation of PERK/Nrf2/HO-1 axis provided protective roles for murine myocardium suffering I/R intervention. METHODS: The in vivo I/R model was formed by ligation of the left anterior descending (LAD) coronary artery of C57BL/6J mice. All animals were assigned into the following groups at random: sham, I/R, rAAV9-PERK + I/R, rAAV9-Nrf2 + I/R, rAAV9-HO-1 + I/R, siRNA-HO-1 + rAAV9-PERK + I/R. The ligation of LAD was released after 30 min of ischemia, which was followed by reperfusion of LAD for 4 h. Then the cardiac tissues and blood serum were collected. TUNEL staining, ELISA assay, TTC staining, Western blotting and real-time PCR were used to determine I/R injury-related indicators. RESULTS: Our results showed that I/R administration triggered cardiomyocytes apoptosis and LDH and CK-MB release, yet overexpression of PERK decreased cellular apoptosis index in the cardiac tissue and reduced levels of LDH and CK-MB in the serum. We further found that the protective actions of PERK against I/R-evoked cardiac damage might be attributed to up-regulation of Nrf2/HO-1 signaling transduction, given that overexpression of Nrf2 and HO-1 ameliorated cardiac cell apoptosis and reduced the size of infarction and ischemia in the myocardial tissue, yet gene silencing of HO-1 invalidated the beneficial roles of PERK overexpression in improving I/R-induced cardiac injury. Then, we investigated whether PERK-activated Nrf2/HO-1 cascade affected endoplasmic reticulum stress (ERS), considering the crucial roles of ERS-associated apoptosis in the development of I/R damage. Our findings indicated that up-regulation of PERK-mediated Nrf2/HO-1 pathway induced the expression reduction of GRP78, CRT, CHOP and caspase-12 both at the transcriptional and translational level. CONCLUSIONS: We, for the first time, discovered that up-regulation of PERK/Nrf2/HO-1 axis improved I/R-induced myocardial injury via reducing ERS-related signal molecules and downstream pro-apoptotic factors. 2020 Cardiovascular Diagnosis and Therapy. All rights reserved.
BACKGROUND: Ischemia-reperfusion (I/R) injury, which leads to additionally cardiac tissue damage, is a severe adverse effect of reperfusion therapeutics used for the treatment of acute myocardial infarction. Agents capable of alleviating I/R-induced myocardial injury are urgently needed. In this study, we investigated whether up-regulation of PERK/Nrf2/HO-1 axis provided protective roles for murine myocardium suffering I/R intervention. METHODS: The in vivo I/R model was formed by ligation of the left anterior descending (LAD) coronary artery of C57BL/6J mice. All animals were assigned into the following groups at random: sham, I/R, rAAV9-PERK + I/R, rAAV9-Nrf2 + I/R, rAAV9-HO-1 + I/R, siRNA-HO-1 + rAAV9-PERK + I/R. The ligation of LAD was released after 30 min of ischemia, which was followed by reperfusion of LAD for 4 h. Then the cardiac tissues and blood serum were collected. TUNEL staining, ELISA assay, TTC staining, Western blotting and real-time PCR were used to determine I/R injury-related indicators. RESULTS: Our results showed that I/R administration triggered cardiomyocytes apoptosis and LDH and CK-MB release, yet overexpression of PERK decreased cellular apoptosis index in the cardiac tissue and reduced levels of LDH and CK-MB in the serum. We further found that the protective actions of PERK against I/R-evoked cardiac damage might be attributed to up-regulation of Nrf2/HO-1 signaling transduction, given that overexpression of Nrf2 and HO-1 ameliorated cardiac cell apoptosis and reduced the size of infarction and ischemia in the myocardial tissue, yet gene silencing of HO-1 invalidated the beneficial roles of PERK overexpression in improving I/R-induced cardiac injury. Then, we investigated whether PERK-activated Nrf2/HO-1 cascade affected endoplasmic reticulum stress (ERS), considering the crucial roles of ERS-associated apoptosis in the development of I/R damage. Our findings indicated that up-regulation of PERK-mediated Nrf2/HO-1 pathway induced the expression reduction of GRP78, CRT, CHOP and caspase-12 both at the transcriptional and translational level. CONCLUSIONS: We, for the first time, discovered that up-regulation of PERK/Nrf2/HO-1 axis improved I/R-induced myocardial injury via reducing ERS-related signal molecules and downstream pro-apoptotic factors. 2020 Cardiovascular Diagnosis and Therapy. All rights reserved.
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