TNF-ALPHA REGULATION OF AT1 RECEPTOR & POST-MI FIBROSIS

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The deposition of fibrous tissue during post-MI remodeling is a critical determinant of cardiac function. Fibrosis is seen initially at the site of myocardial necrosis where development of a replacement scar is an essential component of the wound healing process. Extensive interstitial fibrosis can also develop in non-infarcted segments of the heart. Despite the importance of fibrous tissue deposition in both the scar and in non-infarcted segments of myocardium in determining cardiac function, the mechanisms responsible for post-MI cardiac fibrosis are still poorly understood. Angiotensin (Ang) II appears to play an important role in post-MI fibrosis. Ang II binding with the type I receptor, AT1 activates cardiac fibroblasts and stimulates them to produce proteins and growth factors associated with fibrous tissue deposition. Moreover, AT1 receptor density is increased on cardiac fibroblasts post-MI. Tumor necrosis factor-alpha (TNFalpha) appears in the heart post-MI and there is evidence to suggest that it also is involved in post-MI remodeling. Recent evidence from the investigator's laboratory showing that TNFalpha increases AT1 receptor density on cultured cardiac fibroblasts suggests that an interaction between these systems may be involved in post-MI remodeling. The studies outlined in this proposal will test the significance of this interaction and the mechanisms involved. The specific aims are to determine: 1. the spatial and temporal association between the appearance of TNFalpha, increased AT1 receptor density on cardiac fibroblasts and development of fibrosis throughout post-MI remodeling; 2. if TNFalpha induced AT1 receptor upregulation enhances cardiac fibroblast functions related to post-MI extra cellular matrix remodeling; 3. increased transcription of the AT1A gene by TNFalpha is mediated by activation of NF-kappaB and AP-1, and; 4. if the absence of TNFalpha prevents AT1 receptor upregulation and causes deficient scar formation post-MI. The results are expected to show that TNFalpha upregulation of the AT1 receptor plays an important role in post-MI fibrosis and to identify signal transduction pathways and molecular mechanisms involved in the increase in AT1 receptor density in cardiac fibroblasts. This information will provide important insights into the pathogenesis of post-MI fibrosis.