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.

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.

• Authors: Corey S Moran, Roby J Jose, Erik Biros, Jonathan Golledge
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 34 Issue 12 Pg. 2609-16 (Dec 2014) ISSN: 1524-4636 [Electronic] United States
• PMID: 25301844 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• 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

Topics

• Angiotensin II (metabolism)
• Animals
• Aortic Aneurysm, Abdominal (etiology, metabolism, pathology)
• Aortic Rupture (etiology, metabolism, pathology)
• Apolipoproteins E (deficiency, genetics)
• Blood Pressure (physiology)
• Cathepsins (metabolism)
• Dilatation, Pathologic (etiology, metabolism, 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, genetics, metabolism)
• Pancreatic Elastase (metabolism)
• Proteolysis