title: Inhibition of prolyl 4-hydroxylase prevents left ventricular remodelling in rats with thoracic aortic banding.
abstract: BACKGROUND
  Pressure overload leads to myocardial remodelling with collagen accumulation, left ventricular hypertrophy (LVH), neurohormonal activation and myocardial dysfunction. Prolyl 4-hydroxylases (P4H) are involved in collagen maturation. Inhibition of P4H has been shown to prevent LV remodelling and improve survival post-myocardial infarction.
  
  
  OBJECTIVE
  To evaluate the role of P4H in pressure overload-induced myocardial remodelling.
  
  
  METHODS
  Male Wistar rats underwent thoracic aortic banding (AoB) and were treated with a P4H inhibitor (P4HI) or vehicle (control). Echocardiography and haemodynamic measurements were performed after 4 weeks. Collagens, matrix metalloproteinases (MMP), tissue inhibitors of MMPs (TIMP), growth factors and neurohormonal markers were quantitated in LV samples.
  
  
  RESULTS
  AoB led to LVH, increased LV enddiastolic pressure (LVEDP) and decreased contractility compared to sham. P4HI reversed these effects. AoB increased collagen I and III expression, which was normalized by P4HI. AoB led to deregulation of matrix remodelling enzymes, enhanced expression of growth factors and activation of the endothelin system. P4HI partially prevented deregulation of the MMP/TIMP system, inhibited upregulation of growth factors and normalized AoB-induced ECE-1 and ETB expression.
  
  
  CONCLUSIONS
  P4HI leads to an improvement of AoB-associated LV dysfunction and reduces imbalance of extracellular matrix turnover and hypertrophy-associated gene expression. P4H inhibition could therefore be of value in treatment of myocardial remodelling accompanying pressure overload hypertrophy.
authors.affiliation: Department of Cardiology, CVK, Charite, Universitätsmedizin Berlin, and St. Elisabeth Hospital, Halle, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Fielitz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Philipp
authors.forename: Lars Roman
authors.initials: LR
authors.lastname: Herda
authors.forename: Evelyn
authors.initials: E
authors.lastname: Schuch
authors.forename: Bernhard
authors.initials: B
authors.lastname: Pilz
authors.forename: Carola
authors.initials: C
authors.lastname: Schubert
authors.forename: Volkmar
authors.initials: V
authors.lastname: Günzler
authors.forename: Roland
authors.initials: R
authors.lastname: Willenbrock
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000503:physiopathology*; D024042:Collagen Type I; D024061:Collagen Type III; D005355:Fibrosis / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D053504:Matrix Metalloproteinases, Membrane-Associated; D009206:Myocardium; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012307:Risk Factors; D014463:Ultrasonography
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D011393:Procollagen-Proline Dioxygenase; D053504:Matrix Metalloproteinases, Membrane-Associated