title: Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture in the apolipoprotein E-knockout mouse.
abstract: OBJECTIVE
  Mounting evidence links osteoprotegerin with cardiovascular disease. Elevated serum and aortic tissue osteoprotegerin are associated with the presence and growth of abdominal aortic aneurysm in humans; however, a role for osteoprotegerin in abdominal aortic aneurysm pathogenesis remains to be shown. We examined the functional significance of osteoprotegerin in aortic aneurysm using an Opg-deficient mouse model and in vitro investigations.
  
  
  RESULTS
  Homozygous deletion of Opg in apolipoprotein E-deficient mice (ApoE(-/-)Opg(-/-)) inhibited angiotensin II-induced aortic dilatation. Survival free from aortic rupture was increased from 67% in ApoE(-/-)Opg(+/+) controls to 94% in ApoE(-/-)Opg(-/-) mice (P=0.040). Serum concentrations of proinflammatory cytokines/chemokines, and aortic expression for cathepsin S (CTSS), matrix metalloproteinase 2, and matrix metalloproteinase 9 after 7 days (early-phase) of angiotensin II infusion were significantly reduced in ApoE(-/-)Opg(-/-) mice compared with ApoE(-/-)Opg(+/+) controls. In addition, aortic expression of markers for an inflammatory phenotype in aortic vascular smooth muscle cells in response to early-phase of angiotensin II infusion was significantly lower in Opg-deficient mice. In vitro, human abdominal aortic aneurysm vascular smooth muscle cells produced more CTSS and exhibited increased CTSS-derived elastolytic activity than healthy aortic vascular smooth muscle cells, whereas recombinant human osteoprotegerin stimulated CTSS-dependent elastase activity in aortic vascular smooth muscle cells.
  
  
  CONCLUSIONS
  These findings support a role for osteoprotegerin in aortic aneurysm through upregulation of CTSS, matrix metalloproteinase 2, and matrix metalloproteinase 9 within the aorta, promoting an inflammatory phenotype in aortic vascular smooth muscle cells in response to angiotensin II.
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia (C.S.M., R.J.J., E.B., J.G.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Corey S
authors.initials: CS
authors.lastname: Moran
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia (C.S.M., R.J.J., E.B., J.G.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Roby J
authors.initials: RJ
authors.lastname: Jose
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia (C.S.M., R.J.J., E.B., J.G.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Erik
authors.initials: E
authors.lastname: Biros
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia (C.S.M., R.J.J., E.B., J.G.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.). jonathan.golledge@jcu.edu.au.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001019:Aortic Rupture / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001794:Blood Pressure / Q000502:physiology; D002403:Cathepsins / Q000378:metabolism; D004108:Dilatation, Pathologic / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D053244:Osteoprotegerin / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010196:Pancreatic Elastase / Q000378:metabolism; D059748:Proteolysis
chemical_list: D001057:Apolipoproteins E; D018836:Inflammation Mediators; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D000804:Angiotensin II; D002403:Cathepsins; D010196:Pancreatic Elastase; C028217:cathepsin S; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: aneurysm; cathepsin S; matrix metalloproteinase 2; osteoprotegerin