on July 28, 2005
Published online before print July 28, 2005, doi: 10.1161/01.ATV.0000179600.34086.7d
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Submitted on April 11, 2005
Accepted on June 27, 2005
Lack of the Cysteine-Protease Inhibitor Cystatin C Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice
Eva Bengtsson *;
From the Department of Clinical Sciences (E.B., F.T., L.B., J.N., S.J.), Malmö University Hospital, Sweden; the Department of Clinical Chemistry (A.G., K.H.) and the Department of Cardiology (S.J.), Coronary Program, Heart and Lung Division, Lund University Hospital, and Lund Strategic Research Center for Stem Cell Biology and Cell Therapy (S.J.), Lund University, Sweden.
* To whom correspondence should be addressed. E-mail: eva.bengtsson{at}med.lu.se.
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.
Methods and 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 µm2 per section versus 662 000±19 000 µm2 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.
Key words: atherosclerosis • genetically altered mice • macrophages • cystatin C
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