SIGNAL REGULATION OF CARDIAC CYTOKINE SYNTHESIS AND MECHANICAL FUNCTION

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Studies suggest that TNF synthesis by cardiomyocytes may contribute to cardiac dysfunction in a number of insults including septic shock, thermal injury, congestive heart disease. Compartmentalized TNF production within the heart by be significantly higher than is reflected by systemic TNF levels, and locally produced TNF may not be buffered by circulating TNF receptors which would have limited access to intramyocardially produced TNF. The overall objectives of this proposal are to define the signal transduction mechanisms which regulate posture myocardial TNF production and to define the mechanisms by which TNF altars cardiac function. We hypothesize that phosphorylation and degradation of IkappaB and nuclear translocation of NF-kappaB are critical modulators and posture TNF transcriptional events within the myocardium. We further hypothesize that burn-mediated increases in cardiac TNF synthesis induce a cascade of mediators which contribute to remodeling of the cardiomyocyte cytoskeleton, alter myofibrillar binding to Ca2+ and produce cardiac injury. We will examine the global hypothesis that TNF is a proximal mediator of the overall inflammatory response to burn trauma: Five specific aims will be: 1) determine the effects of burn trauma on myocardial TNF mRNA and protein and determine the cellular source and subcellular location of myocardial TNF synthesis; 2) determine the role of NF-kappaB in posture cardiomyocyte TNF synthesis and identify secretagogues triggered by cutaneous burn injury which regulate NF-kappaB/TNF synthesis; 3) determine the intracellular signaling mechanisms which regulate NF-kappaB ACTIVATION/TNF synthesis; 3) determine the intracellular signaling mechanisms which regulate NF-kappaB activation/TNF synthesis in cardiomyocytes; 4) determine if cardiac derived TNF after burn trauma exerts negative inotropic effects via induction of iNOS, expression of IL-1, or production of cardiac sphingosine; and 5) determine if TNF modulates if TNF modulates cardiac function by altering cellular handling of Ca2+, which in turn, promotes gelsolin-mediated myocyte cytoskeletal remodeling. We will focus on identifying the inducer(s) and signal transduction pathways which lead to TNF secretion by cardiomyocytes as well as specific mechanisms by which TNF produces myocardial injury and dysfunction. These studies should allow development of therapeutic strategies that would provide significant cardioprotection not only for victims of burn trauma but also for patient populations in whom impaired cardiac contraction/relaxation contribute to increased mortality.