Diabetes is now considered a prime risk actor for cardiovascular disease, particularly ischemic heart disease. The risks for myocardial infarction, reinfarction, ischemic heart failure, stroke and the associated mortalities are all significantly increased in diabetes. The pathobiology underlying the excessive and severe ischemic heart disease in diabetes is unclear. Myocardial ischemia-reperfusion (I'R)injury involves both early and late phases. In the early phase, the initial deposition of leukocytes amplifies cardiac injury via an acute inflammatory response. The initial step in acute inflammation is leukocyte, particularly PMN, deposition in the coronary microcirculation. It is not clear how PMNs initially accumulate in the microcirculation, but recent studies suggest that this step is amplified in the diabetic heart following ischemia. Once accumulated, the PMNs activate and produce oxygen free radicals, causing further damage to the vasculature and myocytes. Following ischemia, if PMN deposition is excessive in the diabetic coronary microcirculation an(LIor if diabetic PMNs are hyper-responsive to cytokines released from ischemic tissue, then the severity of leukocytemediated reperfusion injury may be excessive as well. In this project, we will test the hypothesis that diabetes causes alterations in both the blood and the coronary blood vessels. These alterations set the stage for an excessive leukocyte-mediated reperfusion injury in the diabetic heart. If so, then pharmacologically blocking early PMN-mediated inflammation will reduce reperfusion injury and improve the recovery of myocardial contractile function. We will first investigate specific mechanisms, suspected to cause the excessive blood-coronary microvessel interactions observed in diabetes. We will then compare leukocyte adhesion protein characteristics and the """"""""reactivity"""""""" of PMNs to stimulation in Type I and Type II diabetic animals and in patients with Type II diabetes. We will determine if platelets and plasma complement, modulate leukocyte function and leukocyte reactivity in diabetes. The therapeutic potential of limiting leukocyte-mediated inflammation in diabetes will be evaluated. Those pharmacologic agents and antibodies that prove to attenuate the early PMN-mediated response will be tested for efficacy to improve the recovery of myocardial contractile function in the diabetic. The lessons learned from these studies will aid in developing improved therapies to reduce the excessive ischemic heart disease observed in diabetes.
Showing the most recent 10 out of 15 publications
