title: Histone demethylase KDM3a, a novel regulator of vascular smooth muscle cells, controls vascular neointimal hyperplasia in diabetic rats.
abstract: Deregulation of histone demethylase KDM3a, an important regulator for H3K9 methylation, is correlated with obesity and abnormal metabolism in rodent models. However, the function of KDM3a in vascular remodeling under diabetic condition is unknown.
  
  
  
  Adenoviruses expressing KDM3a and lentiviruses expressing KDM3a-targeting siRNA were generated to study the role of KDM3a both in vivo and in vitro. The carotid artery balloon injury model was established in diabetic SD rats to evaluate the significance of KDM3a in vascular injury.
  
  
  
  Diabetic vessels were associated with sustained loss of histone H3 lysine 9 di-methylation (H3K9me2) and elevation of KDM3a. This phenomenon was induced by high glucose (HG) and was persistently present even after removal from diabetic condition and high glucose in vascular smooth muscle cells (VSMCs). After 28-day balloon injury, KDM3a overexpression accelerated while KDM3a knockdown reduced neointima formation, following vascular injury in diabetic rats without glucose control. Microarray analysis revealed KDM3a altered the expression of vascular remodeling genes; particularly, it mediated the Rho/ROCK and AngII/AGTR1 pathways. In the in vivo study, HG and Ang II-stimulated proliferation and migration of VSMCs were enhanced by KDM3a overexpression, whereas markedly prevented by KDM3a knockdown. KDM3a regulated the transcription of AGTR1 and ROCK2 via controlling H3K9me2 in the proximal promoter regions.
  
  
  
  Histone demethylase KDM3a promotes vascular neointimal hyperplasia in diabetic rats via AGTR1 and ROCK2 signaling pathways. Targeting KDM3a might represent a promising therapeutic approach for the prevention of coronary artery disease with diabetes.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Changwu
authors.initials: C
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address: pyh_hongj@163.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000201:enzymology / Q000473:pathology; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008745:Methylation; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology* / Q000473:pathology; D058426:Neointima; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D044140:Receptor, Angiotensin, Type 1; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; C000624330:histone demethylase KDM3a, rat
keywords: Diabetes mellitus; H3K9 methylation; KDM3a; Vascular smooth muscle cell