Leukocyte Cathepsin S Is a Potent Regulator of Both Cell and Matrix Turnover in Advanced Atherosclerosis

被引：56

作者：

de Nooijer, R. ^{[1
,2
]}

Bot, I. ^{[1
]}

von der Thusen, J. H. ^{[1
,3
]}

Leeuwenburgh, M. A. ^{[4
]}

Overkleeft, H. S. ^{[4
]}

Kraaijeveld, A. O. ^{[1
,2
]}

Dorland, R. ^{[1
]}

van Santbrink, P. J. ^{[1
]}

van Heiningen, S. H. ^{[1
]}

Westra, M. M. ^{[1
]}

Kovanen, P. T. ^{[5
]}

Jukema, J. W. ^{[2
]}

van der Wall, E. E. ^{[2
]}

van Berkel, Th. J. C. ^{[1
]}

Shi, G. P. ^{[6
,7
]}

Biessen, E. A. L. ^{[1
,8
]}

机构：

[1] Leiden Univ, Gorlaeus Labs, Leiden Amsterdam Ctr Drug Res, Div Biopharmaceut, NL-2333 CC Leiden, Netherlands

[2] Leiden Univ, Med Ctr, Dept Cardiol, NL-2300 RA Leiden, Netherlands

[3] Univ Amsterdam, Acad Med Ctr, Dept Pathol, NL-1105 AZ Amsterdam, Netherlands

[4] Leiden Univ, Gorlaeus Labs, Div Bioorgan Synth, NL-2300 RA Leiden, Netherlands

[5] Wihuri Res Inst, SF-00140 Helsinki, Finland

[6] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[7] Harvard Univ, Sch Med, Boston, MA USA

[8] Univ Maastricht, Dept Pathol, Maastricht, Netherlands

来源：

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY | 2009年 / 29卷 / 02期

关键词：

atherosclerosis; matrix; cathepsins; leukocytes; apoptosis; SMOOTH-MUSCLE-CELLS; MACROPHAGE APOPTOSIS; ANTIGEN PRESENTATION; INCREASED EXPRESSION; DEFICIENT MICE; HUMAN ATHEROMA; CHOLESTEROL; CYSTEINE; GROWTH; METALLOPROTEINASES;

D O I：

10.1161/ATVBAHA.108.181578

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Objective-A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr-/- mice deficient in leukocyte CatS by transplantation with CatS(-/-) XLDLr-/- or with LDLr-/- bone marrow and administered a high-fat diet. Methods and Results-No difference in aortic root lesion size could be detected between CatS(-/-) and CatS(-/-) chimeras. However, leukocyte CatS deficiency markedly changed plaque morphology and led to a dramatic reduction in necrotic core area by 77% and an abundance of large foam cells. Plaques of CatS(-/-) chimeras contained 17% more macrophages, 62% less SMCs, and 33% less intimal collagen. The latter two could be explained by a reduced number of elastic lamina fractures. Moreover, macrophage apoptosis was reduced by 60% with CatS deficiency. In vitro, CatS was found to be involved in cholesterol metabolism and in macrophage apoptosis in a collagen and fibronectin matrix. Conclusion-Leukocyte CatS deficiency results in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition and may thus be critical in plaque stability. (Arterioscler Thromb Vasc Biol. 2009; 29: 188-194.)

引用

页码：188 / 194

页数：7

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