Submitted on May 15, 2008
Revised on December 29, 2008
Accepted on January 13, 2009
NADPH Oxidase Contributes to Coronary Endothelial Dysfunction in the Failing Heart
Ping Zhang1, Mingxiao Hou1, Yunfang Li1, Xin Xu1, Michel Barsoum, Yingjie Chen1, and Robert J. Bache1*
1 University of Minnesota
* To whom correspondence should be addressed. E-mail: bache001{at}umn.edu.
Increased reactive oxygen species (ROS) produced by the failing heart can react with nitric oxide (NO), thereby decreasing NO bioavailability and contributing to endothelial dysfunction. This study tested the hypothesis that NADPH oxidase is a significant source of ROS that contributes to coronary endothelial dysfunction in the failing heart. Congestive heart failure (CHF) was produced in 6 dogs by ventricular pacing at 240 beats/min for 4 weeks. Studies were performed at rest and during treadmill exercise during control conditions and after NADPH oxidase inhibition with apocynin (4 mg/kg, iv). Apocynin caused no significant changes in heart rate, aortic pressure, LV systolic pressure, LVEDP or LV dP/dtmax at rest or during exercise in either 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 acetylcholine caused dose dependent increases of CBF that were blunted in CHF. Apocynin had no effect on the response to acetylcholine in normal dogs, but augmented the response to acetylcholine in CHF dogs (p<0.05). The oxidative stress markers, nitrotyrosine and 4HNE, were significantly greater in failing than in normal myocardium. Furthermore, superoxide was more than twice normal in failing myocardium and this difference was abolished by blocking NADPH with apocynin. Western analysis of myocardial lysates demonstrated that the p47phox and p22phox subunits were significantly increased in the failing hearts. The findings indicate that ROS produced by NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart.
