COXVIAH, RESPIRATORY CONTROL & MYOCARDIAL FUNCTION

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Our original goal for this subproject was the identification of the specific metabolic components responsible for the cardioprotection function of inducible hsp70 using a transgenic murine line. Our work in both heart and liver has yielded negative results, likely due to the modest elevation in hsp70 by forced gene expression. Upon completion of two manuscripts in progress, we plan to put this project on hold until a transgenic model with more robust gene expression is available. This year, we refocused our efforts to study the hypothesis that there is subcellular compartmentalization of energy stores in the myocardium such that ATP derived glycolytically supports functions different from those supported by ATP derived oxidatively. We are utilizing a series of transgenic murine lines with alterations in gene expression which target pathways in oxidative energy production. These lines include a myoglobin knock-out, a myoglobin over-expressor, and a cytochrome c oxidase (COX) subunit VIaH knock-out. We have completed studies of myocardial performance using the working mouse heart preparation and found, surprisingly, that the myoglobin lines have no distinguishing mechanical phenotype while the COXVIaH knock-out has predominantly diastolic dysfunction. As a consequence of COXVIaH gene knock-out, COX activity is reduced and citrate synthase activity is increased while overall ATP content appears unchanged. Studies are currently underway to establish relative contribution of glycolysis and oxidative phosphorylation to ATP production in this line. Studies are also underway to evaluate the effect on alterations in myoglobin expression on myocardial metabolism and the response to ischemia. (Collaborative 2) REPORT PERIOD: (09/01/97-08/31/98)