title: Neovascularization induced by hypoxia inducible transcription factor is associated with the improvement of cardiac dysfunction in experimental autoimmune myocarditis.
abstract: OBJECTIVE
  Mechanisms of cardiac dysfunction in myocarditis have not been fully elucidated. Though it remains controversial whether angiogenesis is beneficial or harmful in inflammatory disease, significant vascular destruction might possibly impair cardiac function in myocarditis. The prolyl hydroxylase domain-containing protein (PHD) inhibitor is a potential drug for promoting angiogenesis as it stabilizes hypoxia inducible transcription factor (HIF). The authors examine whether the PHD inhibitor TM6008 could affect cardiac function by promoting angiogenesis in experimental autoimmune myocarditis (EAM).
  
  
  METHODS
  EAM was induced on BALB/c mice by immunizing them with a synthesized α myosin heavy-chain peptide. Every day, 200 mg/kg of TM6008 or vehicle was administered orally.
  
  
  RESULTS
  TM6008 improved left ventricular ejection fraction significantly on the 21st day of EAM. Though TM6008 did not affect the severity of myocardial cell infiltration, it tended to reduce cardiac fibrosis. Immunohistochemistry showed that CD31-positive blood vessels were preserved in the TM6008 group compared to the control group. Immunoblotting revealed that TM6008 increased the expression of HIF-1α, HIF-2α and vascular endothelial growth factor in myocarditis.
  
  
  CONCLUSIONS
  Inhibition of PHD could ameliorate cardiac dysfunction in EAM, partially through promoting neovascularization. Relief of tissue hypoxia via neovascularization could improve cardiac function in myocarditis.
authors.affiliation: The University of Tokyo, Department of Cardiovascular Medicine , 7-3-1 Hongo, Bunkyo-ku, Tokyo , Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tada
authors.forename: Masahito
authors.initials: M
authors.lastname: Ogawa
authors.forename: Ryo
authors.initials: R
authors.lastname: Watanabe
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Zempo
authors.forename: Chisato
authors.initials: C
authors.lastname: Takamura
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D003331:Coronary Vessels / Q000502:physiology; D004195:Disease Models, Animal; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D018995:Myosin Heavy Chains / Q000276:immunology; D018919:Neovascularization, Physiologic; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018995:Myosin Heavy Chains; D064800:Prolyl-Hydroxylase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse