Ischemic preconditioning (IPC) and hyperthermia (HT) are known to offer cardioprotection from ischemic injury such as myocardial infarction. While HT induces the heat shock proteins (HSP), which can act as chaperones in preventing myocardial infarction, IPC is known to induce nitric oxide (NO), which can mediate various processes in the heart to minimize ischemic injury. Our preliminary studies with isolated cardiomyocytes have indicated that the HSP90, induced through heat stress, can activate the NOS enzymes. Therefore we hypothesized in the present proposal that HSP90 induced by HT can activate the NOS enzymes in the heat stressed hearts and thus HT and IPC work in a common pathway to minimize the ischemic injury: i.e., in both cases the NOS enzymes are activated to produce high abundance of NO. Since the NO and oxygen have high and equal affinity to the cytochrome c oxidase site in the mitochondria, oxygen consumption and respiration of cardiomyocytes, is expected to be reduced in IPC and heat stressed hearts. However, the role of induced NO in the oxygen consumption in IPC subjected and heat stressed hearts has not been studied before. Thus the main goal of this proposal is to investigate the NO regulated oxygen consumption in PC subjected and heat stressed hearts. We propose to use electron paramagnetic resonance (EPR) oximetry with high sensitive LiPc microcrystals as probe and specially designed EPR instrumentation, to directly measure oxygen consumption in normal, IPC subjected and heat stressed hearts. The present proposal has three main aims: (1) Direct correlation of oxygen consumption and functional recovery in ischemically injured hearts; (2) To study the effect of NO generated during ischemic preconditioning on the myocardial oxygen consumption; (3) To study the role of heat shock proteins, induced by heat stress, on the myocardial oxygen consumption. Using other supporting studies, it would be proved that in both cases (IPC and HT) the NO mediated regulation of respiration is one of the key mechanisms of cardioprotection. Overall, this project will determine the relationship between the NO and the oxygen consumption in the hearts subjected to PC and HT and provide insight into the actual mechanism of cardioprotection. ? ? ?
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