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

Moran, Corey S., Jose, Roby J., Biros, Erik, and Golledge, Jonathan (2014) Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture in the apolipoprotein e-knockout mouse. Arteriosclerosis Thrombosis and Vascular Biology, 34 (12). pp. 2609-2616.

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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.

Item ID: 37051
Item Type: Article (Research - C1)
ISSN: 1079-5642
Keywords: aneurysm, cathepsin S, matrix metalloproteinase 2, osteoprotegerin
Funders: National Institutes of Health (NIH), National Health and Medical Research Council (NHMRC), Queensland Government
Projects and Grants: NHMRC grant 1022752, NHMRC grant 1021416, NHMRC grant 1020955, NHMRC grant 1003707, NHMRC grant 1000967
Date Deposited: 07 Jan 2015 07:36
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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