As a cardiologist interested in the basic mechanisms of myocardial ischemia, my primary career objective is to gain an understanding of the role of disturbed endothelial function in atherosclerosis and how it contributes to abnormalities of vasomotor tone and to thrombosis. My dual training in cell biology and clinical research places me in an advantageous position in this regard, since few cardiologists have developed the necessary skills to apply new insights derived from vascular biology to patients with cardiovascular diseases. This application comes at a crucial point in my career as I complete my transition toward fully independent research status. For this burgeoning interest in closing the gap between basic and clinical research to continue to evolve will require well structured and protected time. The institutional environment will be conducive to this strategy for career development provided that my salary support comes from research sources. The studies presented here focus on defining how the presence of atherosclerosis in the coronary arteries of patients effects endothelium-dependent vasodilator and vasoconstrictor responses. A program of research is proposed that utilizes new insights from the experimental laboratory to address three specific aims. The first will test the hypothesis that endothelial vasodilator dysfunction in human coronary arteries leads to constrictor hyperresponsiveness to catecholamines. The second specific aim will test the hypothesis that endothelium-derived constrictor factors (the polypeptide endothelin, as well as prostanoid factors) are secreted from human atherosclerotic arteries in inappropriately large amounts in response to stimuli known to cause enhanced vasoconstriction and thereby contribute to the development of myocardial ischemia. The third specific aim will examine in patients the concepts derived from experimental studies that aggressive lowering of cholesterol can improve endothelium-dependent vascular function apart from important changes in vessel luminal size. These studies should expand our knowledge of the mechanisms and treatment of abnormal constriction of human coronary arteries, and facilitate clinical attempts to control active ischemia.
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