title: N-Acetylcysteine Attenuates Diabetic Myocardial Ischemia Reperfusion Injury through Inhibiting Excessive Autophagy.
abstract: Background. Excessive autophagy is a major mechanism of myocardial ischemia reperfusion injury (I/RI) in diabetes with enhanced oxidative stress. Antioxidant N-acetylcysteine (NAC) reduces myocardial I/RI. It is unknown if inhibition of autophagy may represent a mechanism whereby NAC confers cardioprotection in diabetes.Methods and Results. Diabetes was induced in Sprague-Dawley rats with streptozotocin and they were treated without or with NAC (1.5 g/kg/day) for four weeks before being subjected to 30-minute coronary occlusion and 2-hour reperfusion. The results showed that cardiac levels of 15-F2t-Isoprostane were increased and that autophagy was evidenced as increases in ratio of LC3 II/I and protein P62 and AMPK and mTOR expressions were significantly increased in diabetic compared to nondiabetic rats, concomitant with increased postischemic myocardial infarct size and CK-MB release but decreased Akt and eNOS activation. Diabetes was also associated with increased postischemic apoptotic cell death manifested as increases in TUNEL positive cells, cleaved-caspase-3, and ratio of Bax/Bcl-2 protein expression. NAC significantly attenuated I/RI-induced increases in oxidative stress and cardiac apoptosis, prevented postischemic autophagy formation in diabetes, and reduced postischemic myocardial infarction (allp< 0.05).Conclusions. NAC confers cardioprotection against diabetic heart I/RI primarily through inhibiting excessive autophagy which might be a major mechanism why diabetic hearts are less tolerant to I/RI.
authors.affiliation: Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Shenzhen People's Hospital, Shenzhen Anesthesiology Engineering Center, The Second Clinical Medical College, Jinan University, Shenzhen, China.
authors.forename: Chunyan
authors.identifier: 0000-0003-1441-5971
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Fuxia
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Science, Guangdong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Haobo
authors.identifier: 0000-0002-5660-7835
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Zhengyuan
authors.identifier: 0000-0002-7002-5524
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Anesthesiology, Shenzhen People's Hospital, Shenzhen Anesthesiology Engineering Center, The Second Clinical Medical College, Jinan University, Shenzhen, China.
authors.forename: Zhongjun
authors.identifier: 0000-0001-6508-512X
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D015237:Dinoprost / Q000031:analogs & derivatives; D020287:In Situ Nick-End Labeling; D028421:Isoprostanes / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D028421:Isoprostanes; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D000111:Acetylcysteine