Adenosine and Pyruvate Protection During Heart Surgery

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DESCRIPTION (provided by applicant): The complication rates of severe ventricular dysfunction, myocardial infarction (MI), heart failure and death after heart surgery, including certain subsets of high-risk CABG surgery patients, may exceed 10-15%. While there are many causes of myocardial injury after heart surgery, ischemia/reperfusion injury and the lack of optimal myocardial protection are important contributing factors that are amenable to improvement. New findings from our laboratory indicate that the cardioprotective effects of adenosine and pyruvate may be mediated via the modulation of mitogen activated protein kinases (MAPK). The purpose of the proposed research is to further elucidate the mechanisms underlying ischemia/reperfusion injury and evaluate the relationship between MAPKs and the cardioprotective effects of acute and delayed adenosine receptor activation and the intermediary metabolite pyruvate. Specific Aim 1 will test the hypothesis that acute and delayed A1receptor preconditioning of the cardiac myocyte during ischemia-reperfusion is mediated via MAPK modulation of mitochondrial function and intracellular Ca++ homeostasis. Specific Aim 2 will determine how adenosine receptor-mediated acute and delayed reduction of infarct size in vivo is mediated via signaling through one or more of the MAPKs. Specific Aim 3 will determine the relationship between adenosine receptor-mediated acute and delayed attenuation of myocardial stunning in vivo and activation of one or more of the MAPK families (p38, ERK, JNK). Specific Aim 4 will determine whether the beneficial effects of pyruvate in reversibly and irreversibly injured myocardium are due to redox modulation of MAPK signaling. Experiments will be performed in isolated rat ventricular myocytes under conditions of simulated ischemia and in in vivo rat infarct and in vivo porcine stunning preparations. In the isolated myocyte studies, fluorescence imaging and confocal microscopy will be used to simultaneously measure changes in myocyte oxidative stress, intramitochondrial free [Ca++], the mitochondria] permeability transition pore (MPTP), mitochondrial membrane potential and changes in mitochondrial redox status. In the in vivo studies, changes in infarct size and myocardial function will be correlated with the expression and activity of the MAPKs in subcellular fractions. It is anticipated the results of these studies will provide new insights regarding mechanisms underlying the salutary effects of adenosine and pyruvate. Ultimately the findings should lead to strategies that will allow for the amplification of the cardioprotective effects of these endogenous agents and/or the development of new and specific therapeutic regimens designed to improve patient outcomes after heart surgery.