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(Circulation Research. 2005;96:368.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Cystatin C Deficiency Increases Elastic Lamina Degradation and Aortic Dilatation in Apolipoprotein E–Null Mice

Galina K. Sukhova, Bing Wang, Peter Libby, Jie-Hong Pan, Yaou Zhang, Anders Grubb, Kenneth Fang, Harold A. Chapman, Guo-Ping Shi

From the Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, Mass; the Department of Medicine (G.K.S., B.W., P.L., G.-P.S.), University of California San Francisco (J.-H.P., Y.Z., K.F., H.A.C.), Calif; and the Department of Clinical Chemistry (A.G.), University of Lund, Sweden.

Correspondence to Guo-Ping Shi, DSc, Cardiovascular Medicine, NRB-7, 77 Ave Louis Pasteur, Boston, MA 02115. E-mail gshi{at}rics.bwh.harvard.edu

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves substantial proteolysis of the arterial extracellular matrix. The lysosomal cysteine proteases can exert potent elastolytic and collagenolytic activity. Human atherosclerotic plaques have increased cysteine protease content and decreased levels of the endogenous inhibitor cystatin C, suggesting an imbalance that would favor matrix degradation in the arterial wall. This study tested directly the hypothesis that impaired expression of cystatin C alters arterial structure. Cystatin C–deficient mice (Cyst C^–/–) were crossbred with apolipoprotein E–deficient mice (ApoE^–/–) to generate cystatin C and apolipoprotein E–double deficient mice (Cyst C^–/–ApoE^–/–). After 12 weeks on an atherogenic diet, cystatin C deficiency yielded significantly increased tunica media elastic lamina fragmentation, decreased medial size, and increased smooth muscle cell and collagen content in aortic lesions of ApoE^–/– mice. Cyst C^–/–ApoE^–/– mice also showed dilated thoracic and abdominal aortae compared with control ApoE^–/– mice, although atheroma lesion size, intimal macrophage accumulation, and lipid core size did not differ between these mice. These findings demonstrate directly the importance of cysteine protease/protease inhibitor balance in dysregulated arterial integrity and remodeling during experimental atherogenesis.

Key Words: cystatin C • apolipoprotein E • cysteine protease • atherosclerosis • smooth muscle cells

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