title: Histone Demethylase JMJD2A Inhibition Attenuates Neointimal Hyperplasia in the Carotid Arteries of Balloon-Injured Diabetic Rats via Transcriptional Silencing: Inflammatory Gene Expression in Vascular Smooth Muscle Cells.
abstract: OBJECTIVE
  Diabetic patients suffer from severe neointimal hyperplasia following angioplasty. The epigenetic abnormalities are increasingly considered to be relevant to the pathogenesis of diabetic cardiovascular complications. But the epigenetic mechanisms linking diabetes and coronary restenosis have not been fully elucidated. In this study, we explored the protective effect and underlying mechanisms of demethylases JMJD2A inhibition in balloon-injury induced neointimal formation in diabetic rats.
  
  
  METHODS
  JMJD2A inhibition was achieved by the chemical inhibitor 2,4-pyridinedicarboxylic acid (2,4-PDCA) and small interfering RNA (siRNA). In vitro, we investigated the proliferation, migration and inflammation of rat vascular smooth muscle cells (VSMCs) in response to high glucose (HG). In vivo, diabetic rats induced using high-fat diet and low-dose streptozotocin (35mg/kg) underwent carotid artery balloon injury. Morphometric analysis was performed using hematein eosin and immumohistochemical staining. Chromatin Immunoprecipitation (ChIP) was conducted to detect modification of H3K9me3 at inflammatory genes promoters.
  
  
  RESULTS
  The global JMJD2A was increased in HG-stimulated VSMCs and balloon-injured arteries of diabetic rats, accompanied by decreased H3K9me3. The inhibition of JMJD2A suppressed VSMCs proliferation, migration and inflammation induced by high glucose (HG) in vitro. And JMJDA2A inhibition attenuated neointimal formation in balloon-injured diabetic rats. The underlying mechanisms were relevant to the restoration of H3K9me3 levels at the promoters of MCP-1 and IL-6, and then the suppressed expression of MCP-1 and IL-6.
  
  
  CONCLUSIONS
  The JMJD2A inhibition significantly attenuated neointimal formation in balloon injured diabetic rats via the suppression of VSMCs proliferation, migration, and inflammation by restoring H3K9me3.
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Wuhan, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Qi
authors.forename: Zhang
authors.initials: Z
authors.lastname: Jing
authors.forename: Wu
authors.initials: W
authors.lastname: Xiaolin
authors.forename: Xu
authors.initials: X
authors.lastname: Changwu
authors.forename: Hu
authors.initials: H
authors.lastname: Xiaorong
authors.forename: Yang
authors.initials: Y
authors.lastname: Jian
authors.forename: Chen
authors.initials: C
authors.lastname: Jing
authors.forename: Jiang
authors.initials: J
authors.lastname: Hong
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D005947:Glucose / Q000494:pharmacology; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D058426:Neointima / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats
chemical_list: D011725:Pyridines; C055293:2,4-pyridinedicarboxylic acid; D056466:Histone Demethylases; C560307:JMJD2A protein, mouse; C000611531:KDM4A protein, rat; D005947:Glucose