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(Circulation. 2004;110:1953-1959.)
© 2004 American Heart Association, Inc.

Genetics

Genetically Determined Resistance to Collagenase Action Augments Interstitial Collagen Accumulation in Atherosclerotic Plaques

Yoshihiro Fukumoto, MD, PhD; Jun-o Deguchi, MD, PhD; Peter Libby, MD; Elena Rabkin-Aikawa, MD, PhD; Yasuhiko Sakata, MD, PhD; Michael T. Chin, MD, PhD; Christopher C. Hill, BA; Patrick R. Lawler, BS; Nerea Varo, PhD; Frederick J. Schoen, MD, PhD; Stephen M. Krane, MD; Masanori Aikawa, MD, PhD

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine (Y.F., J.D., Y.S., M.T.C., C.C.H., P.R.L., N.V.), and the Department of Pathology (E.R.-A., F.J.S.), Brigham and Women’s Hospital, Harvard Medical School, and the Department of Medicine (S.M.K.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Masanori Aikawa, MD, PhD, Brigham and Women’s Hospital, Harvard Medical School, 77 Ave Louis Pasteur, NRB741, Boston, MA 02115. E-mail maikawa{at}rics.bwh.harvard.edu

Received November 6, 2003; de novo received May 24, 2004; accepted May 26, 2004.

Background— We hypothesized that collagenolytic activity produced by activated macrophages contributes to collagen loss and the subsequent instability of atheromatous lesions, a common trigger of acute coronary syndromes. However, no direct in vivo evidence links collagenases with the regulation of collagen content in atherosclerotic plaques.

Methods and Results— To test the hypothesis that collagenases influence the structure of atheromata, we examined collagen accumulation in atherosclerotic lesions of apolipoprotein E-deficient mice (apoE^–/–) that express collagenase-resistant collagen-I (Col^R/R/apoE^–/–, n=12) or wild-type collagen-expressing mice (Col^+/+/apoE^–/–, n=12). Aortic atheromata of both groups had similar sizes and numbers of macrophages, a major source of collagenases. However, aortic intimas from Col^R/R/apoE^–/– mice contained fewer smooth muscle cells, a source of collagen, probably because of decreased migration or proliferation or increased cell death. Despite reduced numbers of smooth muscle cells, atheromata of Col^R/R/apoE^–/– mice contained significantly more intimal collagen than did those of Col^+/+/apoE^–/– mice.

Conclusion— These results establish that collagenase action regulates plaque collagen turnover and smooth muscle cell accumulation.

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