Open AccessTargeting AGGF 1 (angiogenic factor with G patch and FHA domains 1) for Blocking Neointimal Formation After Vascular Injury
Author(s) -
Yao Yufeng,
Hu Zhenkun,
Ye Jian,
Hu Changqing,
Song Qixue,
Da Xingwen,
Yu Yubin,
Li Hui,
Xu Chengqi,
Chen Qiuyun,
Wang Qing Kenneth
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.005889
Subject(s) - restenosis , vascular smooth muscle , neointima , medicine , myocardin , growth factor , cancer research , mapk/erk pathway , stent , microbiology and biotechnology , serum response factor , signal transduction , receptor , biology , transcription factor , smooth muscle , biochemistry , gene
Background Despite recent improvements in angioplasty and placement of drug‐eluting stents in treatment of atherosclerosis, restenosis and in‐stent thrombosis impede treatment efficacy and cause numerous deaths. Research efforts are needed to identify new molecular targets for blocking restenosis. We aim to establish angiogenic factor AGGF 1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury. Methods and Results AGGF 1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF 1 +/− mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells ( VSMC s) in carotid arteries after vascular injury. Importantly, AGGF 1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMC s to the contractile phenotype in mice in vivo. In vitro, AGGF 1 significantly inhibits VSMC s proliferation and decreases the cell numbers at the S phase. AGGF 1 also blocks platelet‐derived growth factor‐ BB –induced proliferation, migration of VSMC s, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF 1 inhibits phenotypic switching of VSMC s to the synthetic phenotype by countering the inhibitory effect of platelet‐derived growth factor‐ BB on SRF expression and the formation of the myocardin/ SRF / CA rG‐box complex involved in activation of VSMC s markers. Finally, we show that AGGF 1 inhibits platelet‐derived growth factor‐ BB –induced phosphorylation of MEK 1/2, ERK 1/2, and Elk phosphorylation involved in the phenotypic switching of VSMC s, and that overexpression of Elk abolishes the effect of AGGF 1. Conclusions AGGF 1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF 1‐ MEK 1/2‐ ERK 1/2‐Elk‐myocardin‐ SRF /p27 signaling pathway.