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 (all p < 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: Sheng Wang, Chunyan Wang, Fuxia Yan, Tingting Wang, Yi He, Haobo Li, Zhengyuan Xia, Zhongjun Zhang
• Journal: Mediators of inflammation (Mediators Inflamm) Vol. 2017 Pg. 9257291 ( 2017) ISSN: 1466-1861 [Electronic] United States
• PMID: 28265179 (Publication Type: Journal Article)

Chemical References

• Isoprostanes
• 8-epi-prostaglandin F2alpha
• Dinoprost
• TOR Serine-Threonine Kinases
• Caspase 3
• Acetylcysteine

Topics

• Acetylcysteine (therapeutic use)
• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Caspase 3 (metabolism)
• Diabetes Mellitus, Experimental (drug therapy)
• Dinoprost (analogs & derivatives)
• In Situ Nick-End Labeling
• Isoprostanes (pharmacology)
• Male
• Myocardial Reperfusion Injury (drug therapy)
• Oxidative Stress (drug effects)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)