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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:188.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

R. de Nooijer; I. Bot; J.H. von der Thüsen; M.A. Leeuwenburgh; H.S. Overkleeft; A.O. Kraaijeveld; R. Dorland; P.J. van Santbrink; S.H. van Heiningen; M.M. Westra; P.T. Kovanen; J.W. Jukema; E.E. van der Wall; Th.J.C. van Berkel; G.P. Shi; E.A.L. Biessen

From the Division of Biopharmaceutics (R.d.N., I.B., J.H.v.d.T., A.O.K., R.D., P.J.v.S., S.H.v.H., M.M.W., T.J.C.v.B., E.A.L.B.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, The Netherlands; the Department of Cardiology (R.d.N., A.O.K., J.W.J., E.E.v.d.W.), Leiden University Medical Centre, The Netherlands; the Department of Pathology (J.H.v.d.T.), Academic Medical Center, Amsterdam, The Netherlands; the Division of Bio-organic Synthesis (M.A.L., H.S.O.), Gorlaeus Laboratories, Leiden University, The Netherlands; Wihuri Research Institute (P.T.K.), Helsinki, Finland; the Department of Medicine (G.P.S.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; and the Department of Pathology (E.A.L.B.), University of Maastricht, The Netherlands.

Correspondence to I. Bot, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. E-mail i.bot{at}lacdr.leidenuniv.nl

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.

To address the role of leukocyte cathepsin-S in advanced lesion composition, we generated chimeric LDLr^–/– mice deficient in leukocyte CatS by transplantation with CatS^–/–xLDLr^–/– or with LDLr^–/– bone marrow. CatS deficiency resulted in considerably altered plaque morphology, with smaller necrotic cores, reduced apoptosis, and decreased SMC content and collagen deposition.

Key Words: atherosclerosis • matrix • cathepsins • leukocytes • apoptosis