Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture in the apolipoprotein E-knockout mouse

Arterioscler Thromb Vasc Biol. 2014 Dec;34(12):2609-16. doi: 10.1161/ATVBAHA.114.304587. Epub 2014 Oct 9.

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.

Approach and 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.

Keywords: aneurysm; cathepsin S; matrix metalloproteinase 2; osteoprotegerin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Animals
  • Aortic Aneurysm, Abdominal / etiology
  • Aortic Aneurysm, Abdominal / metabolism*
  • Aortic Aneurysm, Abdominal / pathology
  • Aortic Rupture / etiology
  • Aortic Rupture / metabolism*
  • Aortic Rupture / pathology
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Blood Pressure / physiology
  • Cathepsins / metabolism
  • Dilatation, Pathologic / etiology
  • Dilatation, Pathologic / metabolism
  • Dilatation, Pathologic / pathology
  • Disease Models, Animal
  • Humans
  • Inflammation Mediators / blood
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Smooth Muscle / metabolism
  • Osteoprotegerin / deficiency*
  • Osteoprotegerin / genetics
  • Osteoprotegerin / metabolism
  • Pancreatic Elastase / metabolism
  • Proteolysis

Substances

  • Apolipoproteins E
  • Inflammation Mediators
  • Osteoprotegerin
  • TNFRSF11B protein, human
  • Tnfrsf11b protein, mouse
  • Angiotensin II
  • Cathepsins
  • Pancreatic Elastase
  • cathepsin S
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse