Effects of abnormal gene expression on accelerated atherosclerosis in Werner syndrome.

沃纳综合征是一种罕见的早衰综合征，伴有严重的动脉粥样硬化。动脉粥样硬化的病因被怀疑是由于其并发症，即糖尿病、高胰岛素血症和高脂血症。但从尸检病例中我们发现，该综合征的动脉粥样硬化机制可能涉及其他一些危险因素。此前我们发现，帕斯敏原激活剂抑制剂-1 (PAI-1) 基因在患有该综合征的患者的皮肤成纤维细胞中过度表达。 PAI-1 是组织纤溶酶原激活剂的有效抑制剂，也是动脉粥样硬化的可能危险因素。这促使我们评估 PAI-1 的血浆浓度。我们的工作假设是，在血浆和成纤维细胞中负责产生 PAI-1 的细胞中，PAI-1 基因上调或未完全抑制。结果显示血浆PAI-1浓度较高。众所周知的诱导PAI-1基因的生理物质之一是肿瘤坏死因子-α（TNF-α），它还诱导其他可能的动脉粥样硬化危险因素、细胞间粘附分子-1（ICAM-1）和血管细胞粘附分子-1。我们发现患有这种综合征的患者血清中 ICAM-1 浓度升高。我们得出结论，血液中高浓度的PAI-1和ICAM-1可能是Werner综合征严重动脉粥样硬化的重要原因之一。

Werner syndrome is a rare premature aging syndrome accompanied by severe atherosclerosis. The etiology of atherosclerosis is suspected to be due to its complications, namely diabetes mellitus, hyperinsulinemia and hyperlipidemia. But from an autopsy case we found that some other risk factors may be involving in the mechanism of atherosclerosis in this syndrome. Previously we revealed that pasminogen activator inhibitor-1 (PAI-1) gene was being overexpressed in skin fibroblasts from a patient with this syndrome. PAI-1 is a potent inhibitor of tissue plasminogen activator and a possible risk factor of atherosclerosis. This led us to assess the plasma concentration of PAI-1. Our working hypothesis was that PAI-1 gene was upregulated or not fully suppressed in cells responsible for the production of PAI-1 in plasma as well as in fibroblasts. The result shown a high concentration of plasma PAI-1. One of well-known physiological substances that induce the PAI-1 gene is tumor necrosis factor-alpha (TNF-alpha), which also induces other possible risk factors of atherosclerosis, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1. We found the serum concentration of ICAM-1 to be elevated in patients with this syndrome. We conclude that high concentration of PAI-1 and ICAM-1 in blood may be one of the potent causes of severe atherosclerosis in Werner syndrome.