title: Propylthiouracil, independent of its antithyroid effect, promotes vascular smooth muscle cells differentiation via PTEN induction.
abstract: 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.
authors.affiliation: First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Fu-Shin Road no 5, Kwei-Shan, Tao-Yuan, 333, Taiwan. wjchen@adm.cgmh.org.tw
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
authors.forename: Dany-Young
authors.initials: DY
authors.lastname: Lee
authors.forename: Lung-An
authors.initials: LA
authors.lastname: Hsu
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Kuo
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020212:Carotid Artery Injuries / Q000188:drug therapy; D002342:Carotid Artery, External / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003285:Contractile Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011441:Propylthiouracil / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D013956:Antithyroid Agents; D003285:Contractile Proteins; D011441:Propylthiouracil; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat