title: N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes.
abstract: N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up-regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process.
authors.affiliation: Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Mao
authors.forename: Haobo
authors.initials: H
authors.lastname: Li
authors.forename: Shigang
authors.initials: S
authors.lastname: Qiao
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Junwen
authors.initials: J
authors.lastname: Wang
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Lei
authors.forename: Zipeng
authors.initials: Z
authors.lastname: Liu
authors.forename: Kwok F J
authors.initials: KF
authors.lastname: Ng
authors.forename: Gordon T
authors.initials: GT
authors.lastname: Wong
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: Michael G
authors.initials: MG
authors.lastname: Irwin
authors.forename: Zhengyuan
authors.initials: Z
authors.lastname: Xia
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D052242:Adiponectin / Q000008:administration & dosage; D000493:Allopurinol / Q000008:administration & dosage; D000818:Animals; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D052242:Adiponectin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009569:Nitric Oxide; D000493:Allopurinol; D019869:Phosphatidylinositol 3-Kinases; D053612:Janus Kinases; D000111:Acetylcysteine
keywords: 15-F2t-IsoP; 15-F2t-isoprostane; ALP; APN; Adiponectin; Antioxidants; C; CK-MB; D; Diabetes; H/R; IS; JAK2/STAT3; Jak2/STAT3; Janus kinase 2/signal transducer and activator of transcription-3; LAD; LDH; Myocardial ischemia injury; N-acetylcysteine; NAC; NO; PI3K/Akt; adiponectin; allopurinol; control; creatinine kinase-MB; eNOS; endothelial nitric oxide synthase; hypoxia/reoxygenation; infarct size; lactate dehydrogenase MI/R, myocardial ischemia reperfusion; left anterior descending; nitric oxide; phosphatidylinositol 3-kinase/Akt; streptozotocin-induced diabetic rats