The long term goal of the proposed research is to deleneate the molecular basis of ischemic and pharmacological preconditioning. It has been repeatedly observed that short period of ischemia protects heart tissues from prolonged ischemic insult, and such an effect is mimicked by a variety of pharmacological agents. Although preconditioning and its blockage are believed to be mediated via openining and closing of the mitochondrial K(ATP) channels, respectively, overall mechanistic feature is not unequivocal. Our preliminary data suggest 5-hydroxydecanoyI-CoA (the CoA-derivative of the potential K(ATP) channel blocker 5-hydroxydecanoic acid) is metabilized via medium chain acyI-CoA dehydrogenase, as well as by the subsequent enzymes of the mitochondrial fatty acid oxidative pathway. The proposed research is based on our hypothesis that the origin of pharmacological preconditioning and its blockage lies in the modulation of enzyme activities of the mitochondrial pathways (viz., fatty acid oxidation and TCA cycle) and the electrontransfer system.
The specific aims of the proposed research are: (1) To elucidate the detailed mechanism for the metabolism of 5-hydroxydecanoyI-CoA (5-HD-CoA) via the enzymes of the mitochondrial oxidative pathway, (2) To determine the effects of 5-HD-CoA and its metabolized products on selected mitochrondrial enzymes, and (3) To investigate the mechanism of production/suppression of reactive oxygen species (ROS) under the influence of selective preconditioning modulators.
These specific aims will be accomplished by employing the techniques of enzyme kinetics, thermodynamics, model building studies involving isolated enzymes and intact mitochonrial preparations. The outcomes of the proposed studies will throw light on the molecular basis of preconditioning and may lead to the development of cardioprotective drugs. ? ?
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