Osteoprotegerin deficiency limits angiotensin II-induced aortic dilatation and rupture in the apolipoprotein e-knockout mouse
Journal Publication ResearchOnline@JCUAbstract
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.
Journal
Arteriosclerosis, Thrombosis and Vascular Biology
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Volume
34
ISBN/ISSN
1079-5642
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Issue
12
Pages Count
8
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Publisher
Lippincott, Williams & Wilkins
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DOI
10.1161/ATVBAHA.114.304587