on July 13, 2006
Published online before print July 13, 2006, doi: 10.1161/01.ATV.0000236428.91125.e6
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Submitted on October 17, 2005
Accepted on June 26, 2006
Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE-/- Mice
Brian J. Bennett ;
From the Department of Pathobiology and the Interdisciplinary Graduate Program in Nutritional Sciences (B.J.B., E.A.K., R.M.V., M.A., M.E.R.), Department of Bioengineering (M.S., C.M.G.), Department of Pathology (S.M.S., C.M.G., M.E.R.), University of Washington, Seattle, Wash; Dipartimento di Medicina Clinica e Sperimentale (M.R.), Università di Padova, Italy.
* To whom correspondence should be addressed. E-mail: ssmjm{at}u.washington.edu.
Objective--Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE-/- mice.
Methods and Results--Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG-/-.apoE-/- mice) at 20, 40, and 60 weeks of age. Littermate OPG+/+.apoE-/- mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG-/-.apoE-/- mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG-/-.apoE-/- mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells.
Conclusion--OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.
Key words: apolipoprotein E-deficient mice • atherosclerosis • osteoprotegerin • vascular calcification
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