THIAZOLIDINEDIONES AND VASCULAR MYOCYTE METABOLISM

动脉粥样硬化性缺血性心脏病是#年的主要死亡原因。 西方工业化国家。尽管由于以下原因导致失败率为30%-50% 随着再狭窄，冠状动脉成形术逐渐成为治疗的首选。 动脉粥样硬化和再狭窄的病理基础是 炎性-纤维增生性重塑过程中血管 平滑肌(VSMC)细胞不适当地去分化、迁移、 作为回应，增殖和合成细胞外基质(ECM)蛋白 到当地释放的多个增长调控因素。结果是 冠状动脉形成梗阻性新的内膜病变。 我们的长期目标是研究人VSMC的功能调节 PDGF和转化生长因子-β1在基础和“合成”条件下。在 合成表型，VSMC表现出高增殖，趋化和 蛋白质的合成特性类似于动脉粥样硬化和 再狭窄病变。这些生长因素对生物多样性指数的影响 增殖(~3H-胸腺嘧啶核苷掺入、c-myc和c-myb表达)， 细胞迁移与蛋白质的数量和质量方面 人工合成的人VSMC的合成将被用作定量评估 体内病理损伤背后的过程。 目前还没有有效的药物来治疗或预防 动脉粥样硬化或再狭窄。噻唑烷二酮类是一类 胰岛素增敏、降血脂、降压药物现状 在这些适应症的人体试验中。这些分子抑制了 鼠类VSMC体外增殖的实验研究我们建议扩大这些研究的范围 对培养的人主动脉VSMC(HAVSMC)进行参数测定 上面。

Atherosclerotic ischemic heart disease is the major cause of death in western industrialized countries. Despite a failure rate of 30-50% due to restenosis, coronary angioplasty is emerging as the treatment of choice. The pathology underlying atherosclerosis and restenosis is an inflammatory-fibroproliferative remodeling process in which vascular smooth muscle (VSMC) cells inappropriately de-differentiate, migrate, proliferate and synthesize extracellular matrix (ECM) proteins in response to multiple growth regulatory factors released locally. The result is formation of obstructive neointimal lesions in the coronary vessels. Our long term goal is to study the functional modulation of human VSMC by PDGF and TGF-beta1 under basal and "synthetic" conditions. In the synthetic phenotype, VSMC exhibit hyper-proliferative, chemotactic and protein synthetic properties similar to those seen in atherosclerotic and restenotic lesions. The effects of these growth factors on indices of proliferation (3H-thymidine incorporation, c-myc and c-myb expression), cell migration and quantitative and qualitative aspects of protein synthesis in synthetic human VSMC will be used as a quantitative estimate of the processes underlying the pathological lesion in vivo. There is no efficacious drug presently available to treat or prevent atherosclerosis or restenosis. The thiazolidinediones are a class on insulin-sensitizing, anti-dyslipidemic, antihypertensive drugs presently in human trials for these indications. These molecules inhibit proliferation of rodent VSMC in vitro. We propose to extend these studies to cultured human aortic VSMC (HAVSMC) measuring the parameters described above.