title: A novel pathway of NADPH oxidase/vascular peroxidase 1 in mediating oxidative injury following ischemia-reperfusion.
abstract: Vascular peroxidase 1 (VPO1) can utilize reactive oxygen species (ROS) generated from NADPH oxidase (NOX) to catalyze peroxidative reactions. This study was performed to identify a novel pathway of NOX/VPO1 in mediating the oxidative injury following myocardial ischemia reperfusion (IR). In a rat model of myocardial IR, the infarct size, serum creatine kinase (CK) activity, apoptosis, NOX activity, NOX2 and VPO1 expression were measured. In a cell (rat heart-derived H9c2 cells) model of hypoxia/reoxygenation (HR), the apoptosis, NOX activity, NOX2 and VPO1 expression, and H(2)O(2) and HOCl levels were examined. In vivo, IR caused 54.8 ± 1.7 % infarct size in myocardium accompanied by elevated activities of CK, caspase-3 and NOX, up-regulated VPO1 expression and high numbers of myocardial apoptotic cells; these effects were attenuated by pretreatment with the inhibitor of NOX. In vitro, inhibition of NOX or silencing of NOX2 or VPO1 expression significantly suppressed HR-induced cellular apoptosis concomitantly with decreased HOCl production. Inhibition of NOX or silencing of NOX2 led to a decrease in H(2)O(2) production accompanied by a decrease in VPO1 expression and HOCl production. However, silencing of VPO1 expression did not affect NOX2 expression and H(2)O(2) production. H(2)O(2)-induced VPO1 expression was partially reversed by JNK or p38 MAPK inhibitor. Our results demonstrate a novel pathway of NOX2/VPO1 in myocardium, where VPO1 coordinates with NOX2 and amplifies the role of NOX-derived ROS in oxidative injury following IR.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.
authors.forename: Yi-Shuai
authors.initials: YS
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: He
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Nian-Sheng
authors.initials: NS
authors.lastname: Li
authors.forename: Xiu-Ju
authors.initials: XJ
authors.lastname: Luo
authors.forename: Chang-Ping
authors.initials: CP
authors.lastname: Hu
authors.forename: Qi-Lin
authors.initials: QL
authors.lastname: Ma
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Zhang
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006420:Hemeproteins / Q000235:genetics / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D006997:Hypochlorous Acid / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006420:Hemeproteins; D008562:Membrane Glycoproteins; D006997:Hypochlorous Acid; D006861:Hydrogen Peroxide; C573339:vascular peroxidase, rat; D010544:Peroxidases; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003402:Creatine Kinase; C505410:Casp3 protein, rat; D053148:Caspase 3