TGF-B1 RECEPTORS IN RESTENOSIS AND AGING

年龄的增长是发展中最重要的因素， 动脉粥样硬化 在接受治疗的30万老年患者中， 冠状动脉粥样硬化的血管成形术发展成纤维增生 6个月内再次闭塞动脉的病变。 的机理 再狭窄是未知的，因此，它对治疗具有抗性。 我们有 确定和年龄相关的血管增殖能力的缺陷， 平滑肌细胞（SMC）与II型受体的特异性丢失相关 转化生长因子-β 1（TGF-β 1）。 这种受体缺陷 使来自老年动物的SMC抵抗TGF-β 1的生长抑制，但 细胞保持其对TGF-β 1的纤维化反应。 我们现在报告， 同样的受体缺陷也发生在人冠状动脉平滑肌细胞中， 动脉粥样硬化斑块 使用逆转录酶-聚合酶链 通过RT-PCR，我们观察到II型TGF-β 1 mRNA的丢失。 动脉粥样硬化SMC中β 1受体。 这些细胞没有生长 抑制对TGF-β 1的反应，但产生胶原蛋白、纤溶酶原 激活剂抑制剂-1，并响应于TGF-β 1而转换肌动蛋白表型。 beta1 II型受体cDNA的转染纠正了异常的 病变衍生细胞的行为。 初步证据显示， 在血管损伤的细胞生长中II型受体的丢失是 由于在复制易出错区域的移码突变， II受体基因，一种最初在结肠癌中发现的缺陷。 由于TGF-β 1在纤维增生性血管病变中过表达， 例如球囊血管成形术后再狭窄，这种选择性生长丧失 抑制功能允许SMC以缓慢、不受控制的方式生长， 并且强烈地有利于细胞外基质积累。 拟议 研究将确定这种受体功能障碍的原因， 方法来诊断它，并开发手段来纠正它。转染 和基因工程受体进入SMC将被测试作为一种手段， 控制再狭窄。 结果将确定原因， 非肿瘤性TGF-β 1受体缺陷的后果，导致 人冠状动脉纤维化和增殖行为失调 SMC。 这种TGF-β 1受体功能障碍直接影响到 动脉粥样硬化、再狭窄和相关的纤维增生性疾病， 在老年人中普遍存在。

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.