ENDOTHELIAL DYSFUNCTION OF HUMAN CORONARY ARTERIOLES

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DESCRIPTION (Adapted from applicant's abstract) The candidate has recently completed a fellowship in Cardiovascular Disease and is currently a full-time junior faculty member in the Department of Internal Medicine at the University of Iowa. He has demonstrated success in basic research of coronary physiology and shows promise of attaining independent status. The proposed studies will be performed in well-funded and established laboratories under the co-sponsorship of Drs. Beverly Davidson and David Gutterman at the University of Iowa. Environmental support and facilities available to him are outstanding. The proposed studies will provide the applicant training in cellular and molecular biology which will allow him to integrate these disciplines and extend his physiologic studies. The training and experience outlined in this proposal will be invaluable in the applicant's goal to be competitive as an academic cardiologist in the field of vascular biology. There are studies of the hypotheses that 1) atherosclerosis impairs endothelium-dependent vasodilation of the human coronary microcirculation as a result of increased oxidative stress, and that 2) vascular dysfunction can be improved by endothelial cell overexpression of superoxide dismutase. The proposal is novel in its study of diseased human coronary microvessels and the use of gene transfer to correct clinically important vascular abnormalities. Isolated atrial or ventricular arterioles, obtained fresh at the time of cardio-pulmonary bypass or cardiac transplant, will be prepared for videomicroscopic examination of internal diameter. The effect of acute (pyrogallol) and chronic (atherosclerosis) oxidative stress on endothelium-dependent dilation will be tested. The mechanism of impaired vasodilation in atherosclerosis will be determined by examining the sensitivity of vascular smooth muscle to nitric oxide and non-nitric oxide stimuli, evaluate the role of vasoconstrictor prostanoids, and assess for decreased cellular levels of SOD in atherosclerosis. The candidate will also determine whether overproduction of superoxide dismutase is protective against reactive oxygen species mediated dysfunction. In-vitro adenoviral transfer of genes for three human SOD isoforms (manganese, copper-zinc, or extracellular), each with specific cellular localization, will be performed in arterioles from patients with and without atherosclerosis. Functional changes of endothelial vasodilation in these vessels will be tested. Preliminary data by the applicant support the feasibility of the proposed studies. Species differences of vascular biology and limitations in animal models of disease underscore the importance of performing these studies. (End of abstract)