title: Modulation of vascular smooth muscle cell phenotype by STAT-1 and STAT-3.
abstract: OBJECTIVE
  Smooth muscle cell (SMC) de-differentiation is a key step that leads to pathological narrowing of blood vessels. De-differentiation involves a reduction in the expression of the SMC contractile genes that are the hallmark of quiescent SMCs. While there is considerable evidence linking inflammation to vascular diseases, very little is known about the mechanisms by which inflammatory signals lead to SMC de-differentiation. Given that the Signal Transducers and Activators of Transcription (STAT) transcriptional factors are the key signaling molecules activated by many inflammatory cytokines and growth factors, the aim of the present study was to determine if STAT transcriptional factors play a role SMC de-differentiation.
  
  
  RESULTS
  Using shRNA targeted to STAT-1 and STAT-3, we show by real time RT-PCR and Western immunoblots that STAT-1 significantly reduces SMC contractile gene expression. In contrast, STAT-3 promotes expression of SMC contractile genes. Over-expression studies of STAT-1 and STAT-3 confirmed our observation that STAT-1 down-regulates whereas STAT-3 promotes SMC contractile gene expression. Bioinformatics analysis shows that promoters of all SMC contractile genes contain STAT binding sites. Finally, using ChIP analysis, we show that both STAT-1 and STAT-3 associate with the calponin gene.
  
  
  CONCLUSIONS
  These data indicate that the balance of STAT-1 and STAT-3 influences the differentiation status of SMCs. Increased levels of STAT-1 promote SMC de-differentiation, whereas high levels of STAT-3 drive SMC into a more mature phenotype. Thus, inhibition of STAT-1 may represent a novel target for therapeutic intervention in the control of vascular diseases such as atherosclerosis and restenosis.
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Mayumi Namekata
authors.initials: MN
authors.lastname: Kirchmer
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Anais
authors.initials: A
authors.lastname: Franco
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Adaia
authors.initials: A
authors.lastname: Albasanz-Puig
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Murray
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yagi
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA.
authors.forename: Zhao Ming
authors.initials: ZM
authors.lastname: Dong
authors.affiliation: Department of Surgery, Division of Vascular Surgery, VA Puget Sound Health Care System and The University of Washington School of Medicine, Seattle, WA, USA. Electronic address: errolw@u.washington.edu.
authors.forename: Errol S
authors.initials: ES
authors.lastname: Wijelath
mesh_terms: D054337:Cell Dedifferentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Oncostatin-M; Phenotype; STAT-1; STAT-3; Smooth muscle cell