Cardiac extracellular matrix (ECM) and vascular adventitial collagen is composed primarily of fibrillar collagen types I and type III. We propose that CD4+ lymphocytes modulate the cardiovascular fibroblast control of the ECM framework and thus affect the compliance of the ventricular and vascular tissues. The efficacy of neuro-endocrine-based therapeutics in clinical cardiovascular pathological conditions suggests that modulation of fibroblast function affects ECM composition. Similarly, we have shown that supematant from cultured T-lymphocytes markedly changes cardiac flbroblast collagen gene expression in vitro. Moreover, our in vivo data suggest that polarization of CD4+ lymphocytes to Th2 subsets results in increased cardiac diastolic and vascular compliance, whereas Thl polarized lymphocytes results in decreased ventricular and vascular compliance. Therefore we propose that changes in the T-lymphocyte cytokine secretory profile appear to directly alter cardiac and vascular fibroblast gene expression and thereby ECM structure and function. To support our hypothesis, we propose to: 1) define the T-lymphocyte mediators that directly affect cardiac fibroblasts and thus diastolic function;2) demonstrate that T-lymphocyte secretory factors directly affect the adventitial fibroblast and therefore vascular compliance;and 3) show that adaptive transfer of immunomodulated T-lymphocytes into nai""""""""ve recipient mice changes the cardiac and vascular fibroblast activity and, accordingly, cardiovascular function. These proposed studies will use our established methods to measure gene-structure-function - specifically, lymphocyte and fibroblast gene expression, supported by protein product analysis, and cardiac and vascular function with in vivo quantification of ventricular and vascular mechanics with the Millar Conductance Catheter System. The potential outcome of these studies will be a discovery of a new and novel pathway that will result in innovative therapeutic approaches for the treatment of hypertension, diastolic dysfunction, and heart failure.
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