title: Adiponectin inhibits oxidative/nitrative stress during myocardial ischemia and reperfusion via PKA signaling.
abstract: The cardioprotective effects of adiponectin (APN) against myocardial ischemia/reperfusion (MI/R) injury are well known. However, comprehension of the mechanisms mediating intracellular APN signaling remains incomplete. We recently demonstrate the antioxidant/antinitrative effects of APN are not dependent on AMPK. Protein kinase A (PKA) has been previously shown to be activated by APN, with uncertain relevance to APN cardiac protection. The current study determined whether the antioxidative/antinitrative effect of APN is mediated by PKA. Administration of APN (2 μg/g) 10 min before reperfusion significantly enhanced cardiac PKA activity, reduced oxidative stress, and decreased infarct size. Knockdown of cardiac PKA expression (PKA-KD) by intramyocardial injection of PKA-siRNAs (>70% suppression) significantly inhibited APN cardioprotection determined by cardiac apoptosis, infarct size, and cardiac function. Moreover, PKA-KD virtually abolished the suppressive effect of APN on MI/R-induced NADPH oxidase overexpression and superoxide overproduction and partially inhibited the effect of APN on nitrative protein modification in MI/R heart. Mechanistically, APN significantly inhibited MI/R-induced IKK/IκB phosphorylation and NF-κB activation, which were blocked in PKA-KD heart. Finally, the PKA-mediated antioxidant/antinitrative and cardioprotective effects of APN are intact in AMPK-deficient mice, suggesting that there is no cross talk between AMPK and PKA signaling in APN cardioprotection. Collectively, we demonstrate for the first time that APN inhibits oxidative/nitrative stress during MI/R via PKA-dependent NF-κB inhibition.
authors.affiliation: Department of Anesthesiology, Shanxi Medical University, Taiyuan, China;
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Wang
authors.forename: Jianli
authors.initials: J
authors.lastname: Zhao
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Wang
authors.forename: Wayne Bond
authors.initials: WB
authors.lastname: Lau
authors.forename: Yue-Xing
authors.initials: YX
authors.lastname: Yuan
authors.forename: Er-He
authors.initials: EH
authors.lastname: Gao
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Xin-Liang
authors.initials: XL
authors.lastname: Ma
mesh_terms: D052242:Adiponectin / Q000008:administration & dosage*; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000235:genetics; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D052242:Adiponectin; D034741:RNA, Small Interfering; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: adiponectin; oxidative stress; protein kinase A; reperfusion injury