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

心肌梗死后重构过程中纤维组织的沉积是心脏功能的关键决定因素。 纤维化最初见于心肌坏死部位，其中替代瘢痕的形成是伤口愈合过程的重要组成部分。 广泛的间质纤维化也可以在心脏的非梗死部分发展。 尽管在心肌的瘢痕和非梗死节段中的纤维组织沉积在确定心脏功能方面的重要性，但对MI后心脏纤维化的机制仍然知之甚少。 血管紧张素（Ang）II似乎在心肌梗死后纤维化中起重要作用。 血管紧张素II与I型受体AT 1结合，激活心脏成纤维细胞并刺激它们产生与纤维组织沉积相关的蛋白质和生长因子。 此外，心肌梗死后心脏成纤维细胞上的AT 1受体密度增加。 肿瘤坏死因子-α（TNF-α）出现在心肌梗死后的心脏中，有证据表明它也参与心肌梗死后的重塑。 最近来自研究者实验室的证据表明，TNF α增加了培养的心脏成纤维细胞上的AT 1受体密度，这表明这些系统之间的相互作用可能涉及MI后重塑。 本提案中概述的研究将检验这种相互作用的意义和所涉机制。 具体目标是确定：1。心肌梗死后重构过程中TNF α的出现、心脏成纤维细胞上AT 1受体密度的增加和纤维化的发展之间的时空相关性; 2.如果TNF α诱导的AT 1受体上调增强与MI后细胞外基质重塑相关的心脏成纤维细胞功能; 3. TNF α对AT 1A基因的转录增加是由NF-κ B和AP-1的激活介导的，以及; 4.如果TNF α的缺乏阻止了AT 1受体上调并导致MI后瘢痕形成不足。 这些结果有望表明，TNF α上调AT 1受体在心肌梗死后纤维化中起重要作用，并确定心脏成纤维细胞中AT 1受体密度增加所涉及的信号转导途径和分子机制。这些信息将为MI后纤维化的发病机制提供重要的见解。

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.