title: Osteopontin-mediated myocardial fibrosis in heart failure: a role for lysyl oxidase?
abstract: OBJECTIVE
  We investigated whether the pro-fibrotic matricellular protein osteopontin (OPN) is associated with the enzymes involved in the extracellular synthesis of fibril-forming collagen type I (i.e. procollagen C-proteinase, PCP) and its cross-linking to form insoluble fibrils (i.e. lysyl oxidase, LOX) in heart failure (HF) of hypertensive origin.
  
  
  RESULTS
  OPN, PCP, and LOX were assessed by histochemical and molecular methods in the myocardium of 21 patients with hypertensive heart disease (HHD) and HF. Whereas the myocardial expression of OPN was very scarce in control hearts (n = 10), it was highly expressed in HF patients (P < 0.0001). OPN was directly correlated with LOX (r = 0.460, P = 0.041), insoluble collagen (r = 0.534, P = 0.015), pulmonary capillary wedge pressure (r = 0.558; P = 0.009), and left-ventricular (LV) chamber stiffness (r = 0.458, P = 0.037), and inversely correlated with LV ejection fraction (r = -0.513, P = 0.017) in all patients. OPN did not correlate with PCP and other parameters assessing collagen synthesis by fibroblasts or degradation by matrix metalloproteinases. In vitro studies showed that OPN significantly (P < 0.05) increases the expression and activity of LOX in human cardiac and dermal fibroblasts.
  
  
  CONCLUSIONS
  An excess of OPN is associated with increased LOX and insoluble collagen, as well as with LV stiffness and systolic dysfunction in patients with HHD and HF. In addition, OPN up-regulates LOX in human fibroblasts. It is suggested that the OPN-LOX axis might facilitate the formation of insoluble collagen (i.e. stiff and resistant to degradation) and the subsequent alteration in LV mechanical properties and function in patients with HHD and HF.
authors.affiliation: Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.forename: Arantxa
authors.initials: A
authors.lastname: González
authors.forename: Diana
authors.initials: D
authors.lastname: Lindner
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Susana
authors.initials: S
authors.lastname: Ravassa
authors.forename: Javier
authors.initials: J
authors.lastname: Beaumont
authors.forename: Idoia
authors.initials: I
authors.lastname: Gallego
authors.forename: Amaia
authors.initials: A
authors.lastname: Zudaire
authors.forename: Cristina
authors.initials: C
authors.lastname: Brugnolaro
authors.forename: Ramón
authors.initials: R
authors.lastname: Querejeta
authors.forename: Mariano
authors.initials: M
authors.lastname: Larman
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
mesh_terms: D000368:Aged; D055395:Bone Morphogenetic Protein 1 / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004548:Elasticity; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D006333:Heart Failure / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000150:complications; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism*; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D011669:Pulmonary Wedge Pressure; D013318:Stroke Volume; D016277:Ventricular Function, Left
chemical_list: C506895:SPP1 protein, human; D053495:Osteopontin; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1
keywords: Fibrosis; Heart failure; Lysyl oxidase; Osteopontin