First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Fu-Shin Road no 5, Kwei-Shan, Tao-Yuan, 333, Taiwan.
Basic Res Cardiol. 2010 Jan;105(1):19-28. doi: 10.1007/s00395-009-0045-z. Epub 2009 Jul 25.
Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial injury.
丙硫氧嘧啶（PTU）除了具有抗甲状腺作用外，最近还发现具有抗动脉粥样硬化作用。本研究旨在确定 PTU 对血管平滑肌细胞（VSMCs）表型调节的影响，因为表型调节可能导致动脉损伤后动脉粥样硬化病变和新生内膜形成的生长。PTU 可减少球囊损伤大鼠颈动脉的新生内膜形成。在体外，PTU 可将 VSMCs 从血清诱导的去分化状态转化为分化状态，表现为梭形形态和收缩蛋白标志物收缩蛋白的表达增加，包括钙调蛋白和平滑肌（SM）-肌球蛋白重链（SM-MHC）。VSMCs 的瞬时转染研究表明，PTU 诱导了 SMC 标志物基因（钙调蛋白和 SM-MHC）启动子的活性，表明 PTU 主要在转录水平上调这些基因的表达。此外，PTU 增强了 PTEN 的表达，而 siRNA 敲低抑制 PTEN 阻断了 PTU 诱导的收缩蛋白表达和启动子活性的激活。在大鼠颈动脉损伤模型中，PTU 逆转了球囊损伤引起的新生内膜中收缩蛋白的下调和 PTEN 的上调。PTU 通过诱导 PTEN 介导的途径促进 VSMC 分化，至少在部分程度上是如此。这些发现提示了 PTU 可能有助于其在动脉损伤后动脉粥样形成和新生内膜形成中的有益作用的一种可能机制。
