Oxygen radicals and nitric oxide (NO) have important roles in cellular signaling and inflammation. Oxygen radical generation is increased in the postischemic heart and is an important cause of postischemic injury. Alterations in NO production also occur and critically contribute to the pathogenesis of postischemic injury. There is increasing evidence that the pathways of oxygen radical and NO generation interact, and that this interaction regulates the cellular production of these critical free radical signaling molecules. However, the exact nature of these interactions and how they modulate postischemic injury is still unknown. Therefore, the goal of this program is to characterize the fundamental interactions between the pathways of oxygen radical and NO generation, and determine how this influences postischemic injury. Studies will be performed first at the enzyme level; then in cells, followed by studies in an in vivo model of coronary occlusion and reflow. There are 5 specific aims. 1) To determine the molecular mechanism by which O2"""""""" and O2"""""""" -derived oxidants affect the function of NO synthase (NOS). 2) To determine the mechanism by which O2~ and O2~ -derived oxidants alter NOS function in the postischemic heart. 3) To characterize the processes and magnitude of NOS-independent NO generation. 4) To characterize the role of NOS-independent pathways of NO generation in the postischemic heart and the mechanisms that regulate this process. 5) Evaluation of the efficacy of new therapies to inhibit oxidant injury and restore NO and NOS function conferring myocardial protection. For these aims; EPR, electrochemical, and chemiluminescence measurements of oxygen radicals, NO, and NO-derived species will be performed along with characterization of the function, expression and modification of the critical NO generating enzymes. Overall, these experiments will determine the interactions between the molecular and cellular pathways of oxygen radical and NO generation in the in vivo postischemic heart and through this knowledge lead to the development of optimal strategies to prevent postischemic injury. ? ?
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