TGF-B1 RECEPTORS IN RESTENOSIS AND AGING

年龄增长是儿童精神分裂症发生发展的最重要因素 动脉硬化。在300,000名老年患者中，超过40%的人接受了 冠状动脉粥样硬化的血管成形术发展成纤维增生性疾病 在6个月内再次闭塞动脉的病变。这其中的机制是 再狭窄是未知的，因此，它一直抵抗治疗。我们有 血管增殖能力的已识别和年龄相关性缺陷 与II型受体特异性丢失相关的平滑肌细胞 转化生长因子-β1(TGF-β1)。这种受体缺陷 使老年动物的SMC抵抗转化生长因子-β1的生长抑制，但 这些细胞保留了对转化生长因子-β1的纤维化反应。我们现在为您报道 同样的受体缺陷也发生在人冠状动脉来源的SMC中 动脉粥样硬化斑块。利用逆转录聚合酶链法 反应(RT-PCR)我们观察到II型转化生长因子-2的mRNA丢失。 动脉粥样硬化性SMC中的β1受体。这些细胞没有生长。 抑制对转化生长因子-β1的反应，但产生胶原和纤溶酶原 激活物抑制因子-1，并转换肌动蛋白表型以响应转化生长因子-1。 Beta1。II型受体基因的转染纠正了这一异常 病变来源细胞的行为。初步证据表明， 血管病变导致的细胞生长过程中II型受体的丢失 由于在该类型的复制错误易感区域中的帧移位突变 II受体基因，最初在结肠癌中发现的缺陷。 由于转化生长因子-β1在纤维增生性血管病变中过度表达， 例如球囊血管成形术后的再狭窄，这种选择性的生长丧失 抑制功能允许SMC以缓慢、不受控制的方式生长， 并且强烈支持细胞外基质的积累。建议数 研究将确定这种受体功能障碍的原因，建立 方法对其进行诊断，并制定相应的矫治方法。转染法 而将基因工程受体植入SMC将作为一种手段进行测试 控制再狭窄。结果将确定原因和 导致非肿瘤性转化生长因子-β1受体缺陷的后果 人冠状动脉纤维化和增殖性行为的失调 SMC。这种转化生长因子-β1受体功能障碍直接影响了 动脉粥样硬化、再狭窄和相关的纤维增生性疾病 在老年人口中很普遍。

Advancing age is the most significant factor in the development of atherosclerosis. More than 40% of the 300,000 elderly patients treated by angioplasty for coronary atherosclerosis develop a fibroproliferative lesion that reoccludes the artery within 6 months. The mechanism of this restenosis is unknown, and thus, it has been resistant to therapy. We have identified and age-related defect in the proliferative capacity of vascular smooth muscle cells (SMC) related to the specific loss of Type II receptors for transforming growth factor-beta1 (TGF-beta1). This receptor defect makes SMC from old animals resistant to growth inhibition by TGF-beta1, but the cells retain their fibrotic responses to TGF-beta1. We now report that this same receptor defect occurs in SMC derived from human coronary atherosclerotic plaques. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we have observed a loss of the mRNA for the Type II TGF- beta1 receptor in atherosclerotic SMC. These cells show no growth inhibitory response to TGF-beta1, but produce collagen, plasminogen activator inhibitor-1, and switch actin phenotypes in response to TGF- beta1. Transfection of Type II receptor cDNA corrects the aberrant behavior of the lesion-derived cells. Preliminary evidence indicates that the loss of the Type II receptor in cells growth from vascular lesions is due to frame-shift mutations in replication error-prone regions of the Type II receptor gene, a defect originally identified in colon carcinoma. Because TGF-beta1 is overexpressed in fibroproliferative vascular lesions, such as restenosis after balloon angioplasty, this selective loss of growth inhibitory function allows the SMC to grow in a slow, uncontrolled fashion, and strongly favors extracellular matrix accumulation. The proposed studies will define the cause of this receptor dysfunction, establish methods to diagnose it, and develop the means to correct it. Transfection and genetically engineered receptors into SMC will be tested as a means of controlling restenosis. th 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 artery SMC. This TGF-beta1 receptor dysfunction has direct implications for atherosclerosis, restenosis, and related fibroproliferative diseases that are prevalent in the elderly population.