Yao Yufeng, Hu Zhenkun, Ye Jian, Hu Changqing, Song Qixue, Da Xingwen, Yu Yubin, Li Hui, Xu Chengqi, Chen Qiuyun, Wang Qing Kenneth
Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Center, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China.
Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH
J Am Heart Assoc. 2017 Jun 25;6(6):e005889. doi: 10.1161/JAHA.117.005889.
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 AGGF1 (angiogenic factor with G patch and FHA domains 1) as a novel target for blocking neointimal formation and restenosis after vascular injury.
AGGF1 shows strong expression in carotid arteries; however, its expression is markedly decreased in arteries after vascular injury. AGGF1 mice show increased neointimal formation accompanied with increased proliferation of vascular smooth muscle cells (VSMCs) in carotid arteries after vascular injury. Importantly, AGGF1 protein therapy blocks neointimal formation after vascular injury by inhibiting the proliferation and promoting phenotypic switching of VSMCs to the contractile phenotype in mice in vivo. In vitro, AGGF1 significantly inhibits VSMCs proliferation and decreases the cell numbers at the S phase. AGGF1 also blocks platelet-derived growth factor-BB-induced proliferation, migration of VSMCs, increases expression of cyclin D, and decreases expression of p21 and p27. AGGF1 inhibits phenotypic switching of VSMCs 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/CArG-box complex involved in activation of VSMCs markers. Finally, we show that AGGF1 inhibits platelet-derived growth factor-BB-induced phosphorylation of MEK1/2, ERK1/2, and Elk phosphorylation involved in the phenotypic switching of VSMCs, and that overexpression of Elk abolishes the effect of AGGF1.
AGGF1 protein therapy is effective in blocking neointimal formation after vascular injury by regulating a novel AGGF1-MEK1/2-ERK1/2-Elk-myocardin-SRF/p27 signaling pathway.
尽管近期血管成形术和药物洗脱支架在动脉粥样硬化治疗方面有所改进，但再狭窄和支架内血栓形成仍会影响治疗效果并导致众多死亡。需要开展研究工作以确定阻止再狭窄的新分子靶点。我们旨在确立血管生成因子AGGF1（含G结构域和FHA结构域的血管生成因子1）作为阻止血管损伤后新生内膜形成和再狭窄的新靶点。
AGGF1在颈动脉中表达强烈；然而，血管损伤后其在动脉中的表达显著降低。AGGF1基因敲除小鼠在血管损伤后颈动脉新生内膜形成增加，同时血管平滑肌细胞（VSMC）增殖增加。重要的是，AGGF1蛋白治疗通过抑制小鼠体内VSMC增殖并促进其表型转换为收缩表型，从而阻止血管损伤后的新生内膜形成。在体外，AGGF1显著抑制VSMC增殖并减少处于S期的细胞数量。AGGF1还可阻断血小板衍生生长因子-BB诱导的VSMC增殖、迁移，增加细胞周期蛋白D的表达，并降低p21和p27的表达。AGGF1通过对抗血小板衍生生长因子-BB对SRF表达的抑制作用以及参与VSMC标志物激活的心肌素/SRF/CArG盒复合物的形成，抑制VSMC向合成表型的表型转换。最后，我们发现AGGF1抑制血小板衍生生长因子-BB诱导的MEK1/2、ERK1/2磷酸化以及参与VSMC表型转换的Elk磷酸化，并且Elk的过表达消除了AGGF1的作用。
AGGF1蛋白治疗通过调节新的AGGF1-MEK1/2-ERK1/2-Elk-心肌素-SRF/p27信号通路，有效阻止血管损伤后的新生内膜形成。
