Estrogen modulation of fibroblast function in the pressure overloaded heart

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DESCRIPTION (provided by applicant): Increased cardiovascular load results in an adaptive process including myocardial hypertrophy and fibrosis. In pathological situations, this adaptive response can progress into myocardial dysfunction and eventually heart failure. Premenopausal females are relatively protected from cardiovascular diseases including loadinduced hypertrophy and heart failure. Recent studies have illustrated that the ovarian hormone, 17 betaestradiol plays an essential role in mediating gender-specific cardioprotection; however, many questions remain regarding the molecular and cellular mechanisms of these effects. Interstitial fibroblasts are critical to myocardial function as these cells produce and remodel the myocardial extracellular matrix. Alterations in the organization and accumulation of the extracellular matrix can deleteriously affect myocardial function and are thought to be important determinants in the progression to heart failure. Little is known regarding the effects of gender and ovarian hormones in the regulation of fibroblast gene expression and function. The proposed studies will determine the effects of gender and 17 beta- estradiol on myocardial fibrosis. These studies will test the over-riding hypothesis that gender-specific differences in the progression of cardiac fibrosis are due to the direct attenuation of the fibroblast response to pro-fibrotic biochemical factors and mechanical forces by 17 beta-estradiol. Specific Aims designed to test this hypothesis include: 1) to determine the effects of gender and 17 beta- estradiol on fibroblast behavior and gene expression in the pressure overloaded myocardium, 2) to determine the mechanisms whereby 17 beta- estradiol represses the pro-fibrotic response of cardiac fibroblasts to angiotensin II and 3) to elucidate the mechanisms through which 17 beta- estradiol attenuates the response of cardiac fibroblasts to mechanical stretch. These studies will utilize whole animal and isolated cell models to assay the effects of gender and 17 beta- estradiol on fibroblast gene expression and behavior (contractility, proliferation and adhesion). The proposed studies will conclusively determine the effects of gender and ovarian hormones on myocardial fibrosis and will begin to elucidate the molecular mechanisms of these effects. These studies will be important towards understanding the cardioprotective mechanisms of gender in heart diseases involving the myocardial interstitium.