During myocardial ischemiz, lypolytic enzymes and lipid metabolites may contribute to the loss of membrane integrity; the sites where enhanced lipolysis occurs in the myocardium are unknown. The structural lipids of all myocardial membranes are condiates for injury by endogenous lipases and free radicals; indeed in critical myocardial membranes, it is uncertain which membrane lipids are most susceptible. Since the sarcolemma is one of the most lipid-rich membranes of the cardiocyte, it may be a major target. The sarcolemma also contains a membrane-bound calcium-sensitive phospholipase A; other sarcolemma enzymes include the Na,K-ATPase, CaATPase and adenylate clycase, all of which may be affected by physical and enzymatic perturbations that may also alter movement of calcium and other ions across the sarcolemma. Inactivation of microsomal retonone-sensitive NADH cytochrome C reductase occurs in ischemic myocardium and the role of free radicals, lipases and lipid metabolites is unclear. The lysosomes of the cardiocyte contain acid-active lipases [e.g. phospholipases A and C] which are capable of hydrolyzing membrane lipids; recent evidence from our laboratory indicates free radical """"""""triggered"""""""" lipolysis of lysosomal phospholipids. Myocardial mitochondrial injury is a well known occurrence during ischemia, but the relevance of free radical and lipolytic mechanisms in this process is unknown. Characterization of the molecular sites [structural lipids] of potential attack by endogenous and exogenous lipolytic enzymes will be the major goal of this proposal. Modulation of free radical and lipolytic mechanisms by lipid metabolites and other metabolic conditions is another important goal; this research will broaden our understanding of the scope of free radical """"""""triggered"""""""" lipolysis in the cardiocyte. We propose to develop in vitro cardiocyte and subcellular membrane systems to enable standardization of the time-course and nature of the above injury processes; then we plan to evaluate interventions [biological and pharmacological] which may retard the process of membrane injury.
Showing the most recent 10 out of 60 publications
