title: STAT4 deficiency protects against neointima formation following arterial injury in mice.
abstract: Signal transducer and activator of transcription 4 (STAT4) has been associated with susceptibility to autoimmune diseases. Intriguingly, we previously reported that STAT4 might play a critical role in vascular smooth muscle cell (VSMC) proliferation. The present study therefore investigated the impact of STAT4 on VSMC migration, apoptosis and neointimal hyperplasia postinjury, as well as the underlying mechanisms. Guide-wire injury was associated with development of intimal neointima, STAT4 and phosphorylated STAT4 (p-STAT4) expressions were apparently up-regulated in the injured arteries. Neointima was greatly blocked in STAT4 knockout (KO) mice compared with wild type (WT) mice. A marked loss of inflammatory cells was identified in the vasculature postinjury in STAT4 KO mice. VSMC apoptosis was enhanced in the vasculature postinjury in STAT4 KO mice compared with WT mice. Cultured primary STAT4 KO VSMCs displayed reduced migration in comparison with WT controls. Mechanically, the deletion of STAT4 potently decreased the level of MCP-1, and its downstream targets MMP1 and MMP2. The effect of STAT4 on VSMC apoptosis was mainly mediated by the activation of the mitochondrial apoptotic pathway, as manifested by increased cytochrome c release and the activation of caspase-3. STAT4 therefore represents a promising molecular target to limit restenosis after artery intervention.
authors.affiliation: Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lv
authors.affiliation: Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China. Electronic address: pudongnanlu@sohu.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Vascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xue
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001013:Aorta, Thoracic / Q000293:injuries / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000293:injuries / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D058426:Neointima / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D061251:Primary Cell Culture; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D017539:Tunica Intima / Q000293:injuries / Q000378:metabolism*; D057772:Vascular System Injuries / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: Apoptosis; Migration; Restenosis; Signal transducer and activator of transcription 4; Vascular smooth muscle cell