title: Gax regulates human vascular smooth muscle cell phenotypic modulation and vascular remodeling.
abstract: Abnormal phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of cardiovascular diseases such as atherosclerosis, hypertension and restenosis after angioplasty. Transcription factors have emerged as critical regulators for VSMCs function, and recently we verified inhibiting transcription factor Gax was important for controlling VSMCs proliferation and migration. This study aimed to determine its role in phenotypic modulation of VSMCs. Western blot revealed that overexpression of Gax increased expression of VSMCs differentiation marker genes such as calponin and SM-MHC 11. Then, Gax overexpression potently suppressed proliferation and migration of VSMCs with or without platelet-derived growth factor-induced-BB (PDGF-BB) stimuli whereas Gax silencing inhibited these processes. Furthermore, cDNA array analysis indicated that Rap1A gene was the downstream target of Gax in human VSMCs. And overexpression of Gax significantly inhibited expression of Rap1A in VSMCs with or without PDGF-BB stimuli. Moreover, overexpression of Rap1A decreased expression of VSMCs differentiation marker genes and increased proliferation and migration of VSMCs with or without PDGF-BB stimuli. Finally, Gax overexpression significantly inhibited the neointimal formation in carotid artery injury of mouse models, specifically through maintaining VSMCs contractile phenotype by decreasing Rap1A expression. In conclusion, these results indicated that Gax was a regulator of human VSMCs phenotypic modulation by targeting Rap1A gene, which suggested that targeting Gax or its downstream targets in human VSMCs may provide an attractive approach for the prevention and treatment of cardiovascular diseases.
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
authors: Hui
authors: H
authors: Zheng
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
authors: Zhenlei
authors: Z
authors: Hu
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
authors: Xinming
authors: X
authors: Zhai
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
authors: Yongyi
authors: Y
authors: Wang
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
authors: Jidong
authors: J
authors: Liu
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
authors: Weijun
authors: W
authors: Wang
authors: Department of Cardiovascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 200127, China.
authors: Song
authors: S
authors: Xue
keywords: Gax; Rap1A; phenotypic modulation; vascular smooth muscle cells