title: NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart.
abstract: Increased reactive oxygen species (ROS) produced by the failing heart can react with nitric oxide (NO), thereby decreasing NO bioavailability. This study tested the hypothesis that increased ROS generation contributes to coronary endothelial dysfunction in the failing heart. Congestive heart failure (CHF) was produced in six dogs by ventricular pacing at 240 beats/min for 4 wk. Studies were performed at rest and during treadmill exercise under control conditions and after treatment with the NADPH oxidase inhibitor and antioxidant apocynin (4 mg/kg iv). Apocynin caused no significant changes in heart rate, aortic pressure, left ventricular (LV) systolic pressure, LV end-diastolic pressure, or maximum rate of LV pressure increase at rest or during exercise in normal or CHF dogs. Apocynin caused no change in coronary blood flow (CBF) in normal dogs but increased CBF at rest and during exercise in animals with CHF (P < 0.05). Intracoronary ACh caused dose-dependent increases of CBF that were blunted in CHF. Apocynin had no effect on the response to ACh in normal dogs but augmented the response to ACh in CHF dogs (P < 0.05). The oxidative stress markers nitrotyrosine and 4-hydroxy-2-nonenal were significantly greater in failing than in normal myocardium. Furthermore, coelenterazine chemiluminescence for O(2)(-) was more than twice normal in failing myocardium, and this difference was abolished by apocynin. Western blot analysis of myocardial lysates demonstrated that the p47(phox) and p22(phox) subunits of NADPH were significantly increased in the failing hearts, while real-time PCR demonstrated that Nox2 mRNA was significantly increased. The data indicate that increased ROS generation in the failing heart is associated with coronary endothelial dysfunction and suggest that NADPH oxidase may contribute to this abnormality.
authors.affiliation: Department of Medicine, University of Minnesota Health Sciences Center, Minneapolis, MN 55455, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Hou
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Michel
authors.initials: M
authors.lastname: Barsoum
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006439:Hemodynamics; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D000447:Aldehydes; D000975:Antioxidants; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D014665:Vasodilator Agents; D013481:Superoxides; C002744:3-nitrotyrosine; D014443:Tyrosine; C056165:acetovanillone; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C027576:4-hydroxy-2-nonenal; D000109:Acetylcholine