title: Canopy 2 attenuates the transition from compensatory hypertrophy to dilated heart failure in hypertrophic cardiomyopathy.
abstract: OBJECTIVE
  A mismatch between adequate angiogenesis and overgrowth of myocytes may be a critical mechanism controlling the transition from adaptive hypertrophy to heart failure. Canopy 2 (CNPY2) was recently identified as a secreted, HIF-1α-regulated angiogenic growth factor. As angiogenic factors play important roles in the development of myocardial hypertrophy, we investigated the role of CNPY2 in molecular and functional changes during development of chronic heart failure using cardiac-specific transgenic (TG) mice that overexpress human CNPY2.
  
  
  RESULTS
  We generated TG mice that constitutively express CNPY2 in the myocardium. Cardiomyopathy was induced in TG and wild-type (WT) mice by transverse aortic constriction (TAC). WT mice developed significant ventricular hypertrophy at 4 weeks and severe dilatation and heart failure at 12 weeks after TAC. However, TG mice preserved much better cardiac structure and function, with less severe ventricular dilatation and markedly reduced cardiac apoptosis and fibrosis following TAC. Excess CNPY2 in TG mice prevented significant loss of vasculature up to 12 weeks after TAC injury, resulting in a better local myocardial environment that facilitated myocyte survival and prevented excessive matrix remodelling compared with WT mice. TG mice had less accumulation of endogenous tumor suppressor p53 after TAC, indicating intrinsic activation of the p53-mediated repression of HIF-1α, and Cnpy2 was diminished in TG mice compared with WT controls.
  
  
  CONCLUSIONS
  Our study showed a correlation between downregulation of endogenous mouse Cnpy2 and p53-mediated HIF-1α inhibition during late-stage hypertrophic development. Additional CNPY2 attenuated the transition from compensatory hypertrophic response to maladaptive ventricular dilatation and heart failure.
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
authors.forename: Anton
authors.initials: A
authors.lastname: Mihic
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
authors.forename: Yuemei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
authors.forename: Kaustabh
authors.initials: K
authors.lastname: Singh
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Dhingra
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.affiliation: Toronto General Research Institute, University Health Network, MaRS Centre, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, Canada M5G 1L7 Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Canada renkeli@uhnres.utoronto.ca.
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001011:Aorta; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications*; D003250:Constriction; D004797:Enzyme-Linked Immunosorbent Assay; D006333:Heart Failure / Q000209:etiology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016276:Ventricular Function / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502333:CNPY2 protein, human; C000603106:Canopy 2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53
keywords: Angiogenesis; CNPY2; HIF-1α; Heart failure; Hypertrophy; p53