The risk of suffering an acute myocardial infarction (AMI) is 3-12 times greater in diabetics compared to non-diabetics. Little is known however, about why diabetics are so vulnerable to ischemic injury. Our laboratory has a long-term interest in the etiology of myocardial ischemia-reperfusion (I/R). In the non-diabetic heart, a leukocyte mediated inflammatory response is known to be a major cause of I/R injury. Inflammation aggravates arteriosclerosis thrombosis and I/R injury. The working hypothesis of this project is that a chronic, low level inflammatory response is associated with type 2 diabetes. This chronic response exacerbates acute ischemic events in the diabetic heart by enhanced platelet and white blood cell deposition, amplifying the oxidative stress during reperfusion following ischemia. We reported that leukocytes deposit in greater numbers in the type 1 diabetic coronary microcirculation during reperfusion and that the blood contribution to reperfusion injury is amplified in a type 1 model of cardiac pump function. We also found that both platelets and white blood cells are chronically activated in type 2 diabetic heart patients and in a genetic animal model of type 2 diabetes. In this renewal, we plan to further explore our working hypothesis in type 2 diabetic animals and patients. Specifically, in Aim 1, we will determine if partially activated platelets modulate leukocyte-mediated reperfusion injury in the type 2 diabetic heart. We will determine if platelet-leukocyte interactions affect leukocyte sequestration in the coronary microcirculation. We will determine if pharmacologic protection of coronary microvascular function translates to improved recovery of cardiac pump function.
In Aim 2, we will test specific cellular and molecular mechanisms by which diabetic platelets are suspected to increase the thrombogenicity of blood and affect inflammatory cell function.
In Aim 3, we will determine if complement enhances I/R injury in the type 2 diabetic heart. Complement contributes to I/R injury in the non-diabetic heart and complement components are chronically activated in diabetes. However, no studies have explored complement deposition in the coronary microcirculation or increased gene expression of myocardial-derived complement as contributors to I/R injury in diabetes. Studies will be performed at the integrative, whole organ level, including direct visualization of blood cellular behavior in the coronary microcirculation and in an in-vivo animal model of AMI. In-vitro cellular and molecular blood studies will be performed to test specific mechanisms by which blood cell function is altered in diabetes. The results will improve our understanding of the role of chronic and acute inflammation in I/R injury in the diabetic heart and suggest new, thoughtful approaches to treat this growing problem. ? ?
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