title: Heat-shock-protein 90 protects from downregulation of HIF-1α in calcineurin-induced myocardial hypertrophy.
abstract: OBJECTIVE
  Capillary/myocyte mismatch is a hallmark of maladaptive myocardial hypertrophy, but the exact mechanisms of this phenomenon remain unknown. We therefore aimed to evaluate the role of calcineurin A in the regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in a calcineurin overexpressing mouse model of myocardial hypertrophy.
  
  
  RESULTS
  Mice overexpressing calcineurin A (CnATg) showed persistent upregulation of HIF-1 alpha protein without evidence of a reduction in capillary density despite progressive myocardial hypertrophy. Likewise, overexpression of calcineurin A in isolated cardiomyocytes induced upregulation of HIF-1 alpha protein. In contrast, NFAT-overexpression had no such effect, implying that NFAT-independent mechanisms were responsible for increased HIF-1 alpha levels. In addition, inhibition of HSP90 via the HSP90-inhibitor 17-AAG or siRNA abolished calcineurin A-induced upregulation of HIF-1 alpha. Consequently, upregulation of HIF-1 alpha target genes like VEGF-A, BNIP-3 or PGK-1 was also inhibited by either 17-AAG or siRNA directed against HSP90. Finally, when CnATg mice were treated with 17-AAG, they demonstrated reduced left ventricular function and capillary density.
  
  
  CONCLUSIONS
  We describe here for the first time that overexpression of the phosphatase calcineurin A prevents the development of a capillary/myocyte mismatch despite progressive myocardial hypertrophy. This effect was mediated by HSP-90 induced stabilization of HIF-1 alpha. Further work is needed to understand this unexpected cardioprotective effect of calcineurin A.
authors.affiliation: Dept. of Cardiology, Angiology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Eschricht
authors.affiliation: Dept. of Cardiology, Angiology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Jarr
authors.affiliation: Dept. of Cardiology and Angiology, University of Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kuhn
authors.affiliation: Dept. of Cardiology, Angiology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Dept. of Cardiology, Angiology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kreusser
authors.affiliation: Dept. of Cardiology, Angiology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Dept. of Cardiology and Angiology, University of Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany. Electronic address: norbert.frey@uk-sk.de.
authors.forename: Norbert
authors.initials: N
authors.lastname: Frey
authors.affiliation: Dept. of Cardiology, Angiology and Pulmology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address: e.chorianopoulos@med.uni-heidelberg.de.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chorianopoulos
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology; D015536:Down-Regulation; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D055550:Protein Stability; D017208:Rats, Wistar; D014158:Transcription, Genetic
chemical_list: D018841:HSP90 Heat-Shock Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050778:NFATC Transcription Factors; D019703:Calcineurin
keywords: Calcineurin A; HIF-1 alpha-angiogenesis; Myocardial hypertrophy