Lack of the cysteine protease inhibitor cystatin C promotes atherosclerosis in apolipoprotein E-deficient mice.
OBJECTIVE
Degradation of extracellular matrix plays an important role in growth and destabilization of atherosclerotic plaques. Cystatin C, inhibitor of the collagen- and elastin-degrading cysteine proteases of the cathepsin family, is produced by virtually all cell types. It is present in the normal artery wall but severely reduced in human atherosclerotic lesions.


RESULTS
To determine the functional role of cystatin C in atherosclerosis, we crossed cystatin C-deficient (cysC(-/-)) mice with apolipoprotein E-deficient (apoE(-/-)) mice. After 25 weeks of atherogenic diet, mice lacking apoE and cystatin C (cysC(-/-) apoE(-/-)) had larger subvalvular plaques compared with cysC(+/+) apoE(-/-) mice (766,000+/-20,000 microm2 per section versus 662,000+/-19,000 microm2 per section; P=0.001), suggesting an atheroprotective role of cystatin C. The plaques from cysC(-/-) apoE(-/-) mice were characterized by increased total macrophage content. To determine which cellular source is important for the antiatherosclerotic effect of cystatin C, we performed bone marrow transplantations. ApoE(-/-) mice were transplanted with either cysC(-/-) apoE(-/-) or cysC(+/+) apoE(-/-) bone marrow. No significant differences in plaque area, macrophage, collagen, or lipid content of subvalvular lesions between the 2 groups were detected.


CONCLUSIONS
The result suggests that the protective role of cystatin C in atherosclerosis is dependent primarily on its expression in nonhematopoietic cell types.
Bengtsson
Eva
E
Department of Clinical Sciences, Malmö University Hospital, Lund University, Sweden. eva.bengtsson@med.lu.se
To
Fong
F
Håkansson
Katarina
K
Grubb
Anders
A
Brånén
Lena
L
Nilsson
Jan
J
Jovinge
Stefan
S
D000818:Animals; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics* / Q000378:metabolism*; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D001057:Apolipoproteins E; C525030:CST3 protein, human; C525031:Cst3 protein, mouse; D055316:Cystatin C; D015891:Cystatins; D003094:Collagen; D002784:Cholesterol