(Verbatim from the application): Brief episodes of sublethal ischemia render the myocardium more resistant against subsequent sustained ischemia and reperfusion: a phenomenon called ischemic preconditioning (PC). The infarct limiting effect of PC is transient, disappearing in 2-3 hrs. However, PC reappears 24 hrs after the initial stimulus, a phenomenon termed as delayed protection. PC occurs following activation of a number of G protein coupled receptors including adenosine (A1 or A3 subtypes), alpha adrenergic, delta1-opioid, free radicals (nitric oxide) and proposed effectors such as the KATP channel openers. While the agonists of these receptors, free radicals as well as KATP channel openers produce immediate (acute) cardioprotective effect, we do not know whether all of them produce delayed protection also. Our goal is to fully characterize the delayed response of these pharmacological trigger(s) and effectors of PC and to understand the complex signal transduction mechanism(s) of late myocardial protection. Our first hypothesis is that pharmacological triggers and effectors of PC induce delayed myocardial protection via nitric oxide (NO)-dependent pathway. We will study the delayed protection by agonists of the receptors (adenosine A1/A3, alpha adrenergic, delta1-opioid,), free radicals and KATP channel openers (diazoxide, pinacidil) in reducing myocardial infarction and apoptosis in the rabbit heart. Role of NO synthase(s) in mediating the delayed protection would be determined by pharmacological inhibition and gene knockout mice. Our second hypothesis is that pharmacological triggers of PC activate signaling pathway leading to phosphorylation of p38, p44 and p42 MAP kinases and also cause their translocation in the nucleus. The third hypothesis is that pharmacological triggers cause activation of nuclear factor kB (NF-kB) via MAP-kinase signaling pathway in the heart. We will show that the pharmacological triggers activate MAP-kinase signaling, that leads to proteolytic degradation of IkB-, release and translocation of NF-kB to the nucleus. Our fourth hypothesis is that activation of NFkB by pharmacological triggers lead to the expression of stress proteins MnSOD, iNOS and Bcl-2 and inhibition of apoptosis. Our fifth hypothesis is that KATP channel openers induce early and delayed ischemic protection via MAP kinase signaling pathway in the heart. These studies will help us learn a great deal on the endogenous mechanisms of delayed preconditioning and assist us in developing innovative techniques leading to one of the most effective means of salvaging ischemic myocardium.
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