title: Osteopontin modulates angiotensin II-induced fibrosis in the intact murine heart.
abstract: OBJECTIVE
  Osteopontin (OPN) is upregulated in left ventricular hypertrophy and is stimulated by angiotensin II (AngII). Our objective was to determine whether mice deficient in OPN would be protected from AngII-induced cardiac fibrosis.
  
  
  BACKGROUND
  Interstitial fibrosis can lead to myocardial dysfunction and ultimately heart failure. Osteopontin activates integrins that regulate cell adhesion, migration, and growth, thus implicating OPN in the process of cardiac fibrosis.
  
  
  METHODS
  Osteopontin null (OPN(-/-)) mice (n = 18) and wild-type controls (n = 20) were infused with AngII (2.5 or 3.0 microg/kg/min) for four days or three weeks via osmotic mini-pumps. Hearts were assessed morphometrically and histologically, including quantitative assessment of fibrosis via optical microscopic imaging analysis. Cardiac fibroblasts derived from these mice were evaluated for adhesion and proliferation. Cardiac transcript expression for cytokines, extracellular matrix (ECM), integrin, and atrial natriuretic peptide were assessed.
  
  
  RESULTS
  Osteopontin(-/-) mice exhibited less cardiac fibrosis (0.7%) than wild-type mice (8.0%) (p < 0.01) and lowered heart/body weight ratios (0.10% vs. 0.23%) (p < 0.01) after three weeks of AngII infusion. Expression of transforming growth factor-beta, fibronectin, and collagen was not different between OPN(-/-) and wild-type mice, despite the decrease in ECM accumulation in the OPN(-/-) mice. Adhesion to ECM substrates decreased by 30% to 50% in cardiac fibroblasts of OPN(-/-) mice but was restored in OPN(-/-) cells by the addition of recombinant osteopontin.
  
  
  CONCLUSIONS
  Osteopontin mediates cardiac fibrosis, probably through the modulation of cellular adhesion and proliferation. Because OPN is increased in cardiac hypertrophy and its lack attenuates fibrosis, understanding of OPN function is essential to extend our knowledge about molecular determinants of cardiac hypertrophy and failure.
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California at Los Angeles, 90095, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Collins
authors.forename: Janet
authors.initials: J
authors.lastname: Schnee
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Sarah
authors.initials: S
authors.lastname: Kim
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Law
authors.forename: Susanne
authors.initials: S
authors.lastname: Nicholas
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
authors.forename: Willa A
authors.initials: WA
authors.lastname: Hsueh
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D051379:Mice; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009124:Muscle Proteins; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D053495:Osteopontin; D012097:Repressor Proteins / Q000187:drug effects / Q000378:metabolism; D012795:Sialoglycoproteins / Q000172:deficiency*; D015854:Up-Regulation / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: C104844:Ankrd1 protein, mouse; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D014662:Vasoconstrictor Agents; D053495:Osteopontin; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor