This study aimed to determine the effect and mechanism of action of adenosine 2 receptor (A2R) activation on myocardial ischemia reperfusion injury (MIRI) under diabetic conditions. MIRI type 2 diabetic rats and H9C2 cardiomyocytes were treated with A2R agonist and then subjected to hypoxia for 6 h and reoxygenation for 18 h. Myocardial damage, and infarct size were determined by cardiac ultrasound. Indicators of cardiomyocyte injury, creatine kinase-MB and cardiac troponin I were detected by Enzyme Linked Immunosorbent Assay. Endoplasmic reticulum stress (ERS) was determined through measuring the expression levels of ERS related genes GRP78, p-IRE1/IRE1, and p-JNKJNK. The mechanism of A2R cardio protection in MIRI through regulating ERS induced autophagy was determined by investigating the ER resident protein IRE-1. The ER-stress inducer Tunicamycin, and the IRE-1 inhibitor STF in combination with the A2R agonist NECA were used, and the cellular responses were assessed through autophagy proteins expression Beclin-1, p62, LC3 and apoptosis. NECA improved left ventricular function post MIRI, limited myocardial infarct size, reduced myocardial damage, decreased cardiomyocytes apoptosis, and attenuated ERS induced autophagy through regulating the IRE-XBP1s-CHOP pathway. These actions resulted into overall protection of the myocardium against MIRI. In summary, A2R activation by NECA prior to ischemia attenuates apoptosis, reduces ERS induced autophagy and restores left ventricular function. This protective effect occurs through regulating the IRE1-XBPs-CHOP related mechanisms. NECA is thus a potential target for the treatment of MIRI in patient with type 2 diabetes.

中文翻译：

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腺苷2受体通过IRE-1信号调节自噬和细胞凋亡减轻2型糖尿病缺血再灌注损伤

本研究旨在确定腺苷 2 受体 (A2R) 激活对糖尿病条件下心肌缺血再灌注损伤 (MIRI) 的影响和作用机制。MIRI 2 型糖尿病大鼠和 H9C2 心肌细胞用 A2R 激动剂处理，然后缺氧 6 小时，复氧 18 小时。心肌损伤和梗塞面积通过心脏超声确定。采用酶联免疫吸附法检测心肌细胞损伤指标、肌酸激酶-MB和心肌肌钙蛋白I。通过测量 ERS ​​相关基因 GRP78、p-IRE1/IRE1 和 p-JNKJNK 的表达水平来确定内质网应激 (ERS)。通过研究 ER 驻留蛋白 IRE-1，确定了通过调节 ERS ​​诱导的自噬来保护 MIRI 中 A2R 心脏的机制。使用 ER 应激诱导剂衣霉素和 IRE-1 抑制剂 STF 与 A2R 激动剂 NECA 的组合，并通过自噬蛋白表达 Beclin-1、p62、LC3 和细胞凋亡评估细胞反应。NECA 通过调节 IRE-XBP1s-CHOP 通路改善 MIRI 后的左心室功能，限制心肌梗死面积，减少心肌损伤，减少心肌细胞凋亡，并减弱 ERS ​​诱导的自噬。这些行动导致心肌免受 MIRI 的全面保护。总之，NECA 在缺血前激活 A2R 会减弱细胞凋亡，减少 ERS ​​诱导的自噬并恢复左心室功能。这种保护作用通过调节 IRE1-XBPs-CHOP 相关机制发生。