Advancing age is the single strongest risk factor for the development of atherosclerosis Underlying atherosclerosis is the major predisposing factor to both myocardial infarction and stroke. Several lines of evidence suggest that atherosclerotic lesions are chronically healing wounds, that for unknown reasons, fail to regress. We have identified an age-related defect in the proliferative and apoptotic responses of rat and human vascular smooth muscle cells (SMC) that would impair their ability to undergo regression when presented with appropriate signals. This resistance to apoptotic regression is related to the specific loss of Type II receptors (TbetaR-2) for transforming growth factor-beta1 (TGF-beta1). Reduced expression of TbetaR-2 makes SMC from old animals and from human atherosclerotic lesions resistant to growth inhibition and apoptosis induced by TGF-beta1. In some patients, loss of the Type II receptor is due to frame-shift mutations in TbetaR-2. However, most lesion cells are resistant due to reduced transcription of TbetaR-2. Using genomic arrays, it was determined that human lesions, and lesion cell lines, over express Egr-1, a about zinc-finger transcription factor that controls key stress-responsive genes. In new studies, we demonstrate that Egr-1 is a strong transcriptional suppressor of the TbetaR-2 promoter, and confers resistance to TGF-beta. The proposed studies will define the mechanism by which Egr-1 suppresses TbetaR-2, determine the cause of the elevated Egr-1, and determine downstream consequences of elevated Egr-1 in lesion cells. By defining the cause and mechanisms of Egr-1-induced resistance, we plan to develop the means to correct it. Transplantation of genetically modified SMC will be used to evaluate the role of elevated Egr-1 and TGF-beta resistance in the development of age-related intimal hyperplasia. The results will identify the causes and consequences of a non-neoplastic TGF beta1 receptor defect that leads to dysregulated fibrotic and proliferative behavior in human coronary and carotid artery SMC. This age-related TGF-beta1 receptor dysfunction is a component of a broad resistance to inhibition in these cells and thus, is potentially directly involved in the development of atherosclerosis, restenosis, and related fibroproliferative diseases that are prevalent in the elderly population.
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