title: Cystatin C deficiency increases elastic lamina degradation and aortic dilatation in apolipoprotein E-null mice.
abstract: 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.
authors.affiliation: Donald W. Reynolds Cardiovascular Clinical Research Center, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, Mass, USA.
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Jie-Hong
authors.initials: JH
authors.lastname: Pan
authors.forename: Yaou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Anders
authors.initials: A
authors.lastname: Grubb
authors.forename: Kenneth
authors.initials: K
authors.lastname: Fang
authors.forename: Harold A
authors.initials: HA
authors.lastname: Chapman
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000737:chemistry* / Q000378:metabolism* / Q000473:pathology; D001013:Aorta, Thoracic / Q000737:chemistry* / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000209:etiology / Q000235:genetics; D001485:Basement Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D055316:Cystatin C; D015891:Cystatins / Q000172:deficiency*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004108:Dilatation, Pathologic / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; C525030:CST3 protein, human; C525031:Cst3 protein, mouse; D055316:Cystatin C; D015891:Cystatins; D003094:Collagen; D003546:Cysteine Endopeptidases