title: Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II.
abstract: Reactive oxygen species (ROS) participate in cardioprotection of ischemic reperfusion (I/R) injury via preconditioning mechanisms. Mitochondrial ROS have been shown to play a key role in this process. Angiotensin II (Ang II) exhibits pharmacological preconditioning; however, the involvement of NAD(P)H oxidase, known as an ROS-generating enzyme responsive to Ang II stimuli, in the preconditioning process remains unclear. We compared the effects of 5-hydroxydecanoate (5-HD; an inhibitor of mitochondrial ATP-sensitive potassium channels), apocynin (an NAD(P)H oxidase inhibitor), and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol; a membrane permeable radical scavenger) on pharmacological preconditioning by Ang II in rat cardiac I/R injury in vivo. Treatment with a pressor dose of Ang II before a 30-minute coronary occlusion reduced infarct size as determined 24 hours after reperfusion. The protective effects of Ang II were eliminated by pretreatment with 5-HD or apocynin, similar to tempol. Both 5-HD and apocynin suppressed the enhanced cardiac lipid peroxidation and activation of the apoptosis signal-regulating kinase/p38, c-Jun NH2-terminal kinase (JNK) pathways, but not the Raf/MEK/extracellular signal-regulated kinase pathway, elicited by acutely administered Ang II. Apocynin but not 5-HD suppressed Ang II-induced augmentations of the NAD(P)H oxidase complex formation (p47phox, p22phox, and Rac-1) and its activity in the heart. Finally, 5-HD suppressed superoxide production by isolated cardiac mitochondria without any effect on their respiration. These results suggest that the preconditioning effects of Ang II for cardiac I/R injury may be mediated by cardiac mitochondria-derived ROS enhanced through NAD(P)H oxidase via JNK and p38 mitogen-activated protein kinase activation.
authors.affiliation: Department of Pharmacology, Kagawa University Medical School, Miki, Kagawa, Japan. kimura@kms.ac.jp
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Guo-Xing
authors.initials: GX
authors.lastname: Zhang
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Takatomi
authors.initials: T
authors.lastname: Shokoji
authors.forename: Li
authors.initials: L
authors.lastname: Yao
authors.forename: Yu-Yan
authors.initials: YY
authors.lastname: Fan
authors.forename: Matlubur
authors.initials: M
authors.lastname: Rahman
authors.forename: Takeo
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hajime
authors.initials: H
authors.lastname: Maeta
authors.forename: Youichi
authors.initials: Y
authors.lastname: Abe
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D003652:Decanoic Acids / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010586:Phagocytes / Q000201:enzymology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000037:antagonists & inhibitors
chemical_list: D000098:Acetophenones; D002316:Cardiotonic Agents; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D017382:Reactive Oxygen Species; D013481:Superoxides; D000804:Angiotensin II; C052853:5-hydroxydecanoic acid; C056165:acetovanillone; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases