We propose to explore the mechanisms by which chronic hyperglycemia reduces cardioprotection. It has been shown in numerous epidemiologic studies that diabetes accelerates atherosclerosis in both men and women. Several mechanisms have been proposed to explain how chronic hyperglycemia can contribute to coronary heart disease, but definitive mechanisms have yet to be proven. We propose to chemically induce chronic hyperglycemia in cynomolgus monkeys which we have previously shown to be excellent models of atherosclerosis and coronary heart disease. We will specifically evaluate the effect of direct chronic hyperglycemia on the accumulation of glycated and advanced glycated end-products in the arterial wall and its specific relationship to coronary vascular reactivity and atherosclerosis. In addition, due to the prospective nature of the study, the relationship between other factors such as insulin resistance and lipoprotein concentrations and metabolism, and the effects on vascular reactivity and atherosclerosis can be assessed in this study. Therefore, the significance of this proposal is that it will allow a direct investigation of the effects of chronic hyperglycemia on mechanisms of coronary heart disease in a well-characterized model of atherosclerosis.
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