Cardiac surgery is associated with changes in vasomotor control which is associated with increased morbidity and mortality. This is especially true after heart operations involving cardioplegia and cardiopulmonary bypass (CPB). Recently, we have reported alterations in microvascular signal transduction and an upregulation and downregulation of specific genes in the myocardium after heart surgery involving blood cardioplegia and CPB. However, most of these studies have been performed in animal models. Since alterations in vasomotor regulation and function are critical aspects contributing to morbidity of cardioplegia and CPB, a better understanding of the regulation of the coronary microvasculature of these patients may lead to improved outcomes after cardiac surgery. The goal of the proposed research is to determine the effect of cardioplegia and CPB on alterations in signal transduction associated with vascular function that occur in human patients undergoing heart surgery. Specifically, we will determine the roles of protein kinase / phosphatase activities, mitogen activated protein kinases, protein kinase C, and expression of inducible cyclooxygenase-2 in mediating acute changes in coronary microvascular reactivity during clinical cardiac surgery. Changes in myogenic contraction and endothelium-dependent and endothelium-independent agonist induced arteriolar vasomotor responses of the coronary microcirculation will be examined after cardioplegia and CPB, and after exposure of vessels in vitro to increased oxidative stress and inflammatory cytokines to confirm the mechanisms contributing to the findings from vessels harvested from patients. Finally, poly(ADP-ribose) polymerase (PARP) has been demonstrated to cause endothelial dysfunction and other vascular injury in patients. Thus, we will examine the changes in nitrosative stress, PARP activation and apoptosis inducing factor translocation after cardioplegia and CPB. This work will be accomplished through an exhaustive approach using molecular and cellular biology techniques to examine the protein and gene expressions involved in maintaining vascular integrity in clinical cardiac surgery involving cardioplegia / CPB. All of the methods described in the proposal have been utilized by the PI previously, and are standard and consistent preparations that have been subjected to extensive peer review. The results of these studies may have significant implications regarding the recovery of patients undergoing clinical cardiac surgery. ? ?
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