Angiogenic Factor With G Patch and FHA Domains 1 Is a Novel Regulator of Vascular Injury.
Phenotypic modulation of vascular smooth muscle cells represents a hallmark event in vascular injury. The underlying mechanism is not completely sorted out. We investigated the involvement of angiogenic factor with G patch and FHA domains 1 (Aggf1) in vascular injury focusing on the transcriptional regulation of vascular smooth muscle cell signature genes.



We report here that Aggf1 expression was downregulated in several different cell models of phenotypic modulation in vitro and in the vessels after carotid artery ligation in mice. Adenovirus-mediated Aggf1 overexpression dampened vascular injury and normalized vascular smooth muscle cell signature gene expression. Mechanistically, Aggf1 interacted with myocardin and was imperative for the formation of a serum response factor-myocardin complex on gene promoters. In response to injurious stimuli, kruppel-like factor 4 was recruited to the Aggf1 promoter and enlisted histone deacetylase 11 to repress Aggf1 transcription. In accordance, depletion of kruppel-like factor 4 or histone deacetylase 11 restored Aggf1 expression and abrogated vascular smooth muscle cell phenotypic modulation. Finally, treatment of a histone deacetylase 11 inhibitor attenuated vascular injury in mice.



Therefore, we have unveiled a previously unrecognized role for Aggf1 in regulating vascular injury.
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Bisheng
B
Zhou
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Sheng
S
Zeng
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Nan
N
Li
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Liming
L
Yu
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Guang
G
Yang
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Yuyu
Y
Yang
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Xinjian
X
Zhang
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Mingming
M
Fang
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.).
Jun
J
Xia
From the Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China (B.Z., S.Z., N.L., L.Y., G.Y., X.Z., Y.X.); State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing (Y.Y.); Department of Nursing, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.); and Department of Respiratory Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China (J.X.). yxu2005@gmail.com ricsummer@163.com.
Yong
Y
Xu
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002460:Cell Line; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000099251:Myocardin
D042501:Angiogenic Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D026362:Serum Response Factor; D015534:Trans-Activators; D000099251:Myocardin; C482200:AGGF1 protein, human; C000620722:AGGF1 protein, rat; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; C476858:SRF protein, human; C462506:HDAC11 protein, human
carotid arteries; epigenetics; histone deacetylases; muscle, smooth, vascular; serum response factor