Oxidants and Nitric Oxide in Post-Ischemic Heart Injury

Johns Hopkins University, Baltimore MD

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Abstract

Oxygen radical generation is increased in the postischemic heart and leads to altered nitric oxide (NO)[unreadable] production and postischemic injury. Using Electron Paramagnetic Resonance (EPR) and other techniques,[unreadable] we directly measured the mechanisms of oxygen radical and NO generation in the postischemic heart.[unreadable] From these and other recent studies, it has been shown that oxidants alter NO generation from nitric oxide[unreadable] synthase (NOS). However, the precise role of oxidants in the regulation of NOS structure and function[unreadable] remains unknown. Recently, it has been shown that under ischemic conditions oxygen radical generating[unreadable] enzymes, such as xanthine oxidase (XO), also form NO through reduction of nitrite or nitrate. However, the[unreadable] nature and role of NOS-independent pathways of NO formation in the modulation of postischemic injury is[unreadable] unclear. Therefore, this project will characterize these processes of NO formation and their oxidant[unreadable] interactions. Studies will be performed first at the enzyme level; then in endothelial cells, followed by[unreadable] studies in isolated heart models and finally in vivo models of coronary occlusion and reflow. This project[unreadable] has the following 5 specific aims. 1) To characterize mechanisms by which 'O2~ and 'O2~ -derived oxidants[unreadable] affect the structure and function of human endothelial NOS (eNOS). 2) To determine the mechanism by[unreadable] which -O2" and 'O2 -derived oxidants alter eNOS structure and function in the isolated postischemic heart[unreadable] and evaluate approaches to restore eNOS function. 3) To characterize fundamental mechanisms of nitrite,[unreadable] nitrate or organic nitrate mediated NO generation. 4) To characterize the role of nitrite or nitrate mediated[unreadable] pathways of NO generation in the isolated postischemic heart and the mechanisms that regulate this[unreadable] process. 5) In vivo testing and EPR/NMR coimaging of novel therapeutics to inhibit oxidant injury, restore[unreadable] NOS function and confer myocardial protection. For these aims; EPR, electrochemical, and[unreadable] chemiluminescence measurements of oxygen radicals, NO, and NO derived species will be performed[unreadable] along with characterization of the function, structure and modification of the critical NO generating[unreadable] enzymes. Overall, this project will determine the interactions between oxygen radicals and the pathways of[unreadable] NO generation that occur in the process of postischemic injury, and lead to the development of optimal[unreadable] strategies to salvage heart muscle at risk.