During the process of myocardial ischemic injury highly reactive species of free radicals may be generated and may interact with membranes and cells of myocardial tissue. The major cell types of the heart are the cardiocytes, smooth muscle and endothelial cells all of which are potential targets for free radical damage. This proposal will attempt to identify the ability of each of these cell types to generate endogenous free radicals; in addition, this proposal will focus on the susceptibility of each of these cell types to injury to both endogenous and exogenously generated free radicals. Identification of the nature of these radicals in the myocardium requires electron paramagnetic resonance spectroscopy (EPR) and suitable techniques for spin trapping transient radicals. At the subcellular level, lipid-rich sarcolemma (SL) and plasmalemma (PL) of these three cell types may be major targets for free radical induced injury; this proposal will attempt to correlate enzymatic and functional changes of the SL and PL and to evaluate interventions that might protect against such injury. Our lysosomal model will continue to be studied and, where feasible, lysosomes from the three cell types will be tested for their susceptibility to free radical injury. In addition to the cellular and membrane models above, we plan to evaluate the effects of endogenous and exogenously generated free radicals on arterial vascular tension to test the ability of interventions to retard injury in this model. Recent studies of impaired lipid metabolism during ischemia have suggested that amphiphiles, such as acyl CoA, acyl caritine, and lysophospholipids, are mediators of injury. Since major molecular sites of free radical attack are the unsaturated bonds of myocardial membrane lipids, a major goal of this proposal will be to seek interactions between lipid amphiphiles and myocardial lipases that might alter the susceptibility of free radical-perturbed myocardial membrane lipids to lipolytic enzyme attack. In addition, products of free radial-induced scission of myocardial lipids may be toxic; identification of these products may permit in vitro studies of their effects on cells and membranes. The above molecular approach may enable more precise evaluation of agents, both free-radical quenching and antilipolytic, that may retard the injury of the ischemic myocardium.
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| Arroyo, C M; Kramer, J H; Leiboff, R H et al. (1987) Spin trapping of oxygen and carbon-centered free radicals in ischemic canine myocardium. Free Radic Biol Med 3:313-6 |
