There is increasing evidence implicating xanthine oxidase-derived oxidative stress (OS) in heart failure (HF) pathophysiology. Formation of free radicals may be directly toxic to cells via apoptotic and/or oncotic mechanisms. In addition, OS may modify protein function either reversibly or irreversibly, thereby altering cellular function. Xanthine oxidase (XO), which produces superoxide as a byproduct of purine metabolism, is emerging as a key source of both myocardial and vascular OS. In this regard, inhibition of XO profoundly increases myocardial mechanoenergetic efficiency (the ratio of myocardial work to oxygen consumed; SW/MVO2) in HF. The effects of XO inhibition occur at least in part, at the level of myofilament Ca2+ responsiveness and involve interactions with cardiac nitric oxide. In preliminary data contained within this grant, we advance the mechanistic underpinnings of XO activity in the failing heart, and provide evidence that XO may both impair cardiac excitation-contraction coupling and participate in cardiac remodeling. Thus, the experiments proposed in this competitive renewal will further advance understanding mechanisms and manifestations of cardiac oxidative stress. The results of these studies will clarify pathophysiologic consequences of oxidant stress in heart failure and may have therapeutic implications.
Our specific aims will test the hypotheses that cardiac XO activity participates in deranged cardiac EC coupling and remodeling. In addition, we will delineate the mechanism for nitric oxide OS interactions in the heart by testing the prediction that cardiac neuronal NOS regulates XO activity. These studies proposed will provide mechanistic insight into the role of oxidant stress in depressed E-C coupling and LV remodeling in HF. Finally, the present studies in 3 highly relevant animal models will provide mechanistic insights complementary to those expected from ongoing clinical trials designed to test the utility of XO inhibitors in human HF therapy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Adhikari, Bishow B
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University of Miami School of Medicine
Internal Medicine/Medicine
Schools of Medicine
Coral Gables
United States
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