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

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−/−×LDLr−/− 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.

[1]  D. Watkins,et al.  Destabilizing Role of Cathepsin S in Murine Atherosclerotic Plaques , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[2]  T. Henry,et al.  Extracellular Proteases in Atherosclerosis and Restenosis , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[3]  A. Newby,et al.  Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. , 2005, Physiological reviews.

[4]  Wei Li,et al.  Increased Expression and Translocation of Lysosomal Cathepsins Contribute to Macrophage Apoptosis in Atherogenesis , 2004, Annals of the New York Academy of Sciences.

[5]  P. Kovanen,et al.  Proteolysis of the Pericellular Matrix: A Novel Element Determining Cell Survival and Death in the Pathogenesis of Plaque Erosion and Rupture , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[6]  D. Spero,et al.  Cysteine protease cathepsin S as a key step in antigen presentation. , 2004, Drug news & perspectives.

[7]  I. Tabas,et al.  Apoptosis and plaque destabilization in atherosclerosis: the role of macrophage apoptosis induced by cholesterol , 2004, Cell Death and Differentiation.

[8]  X. Cheng,et al.  Increased expression of elastolytic cysteine proteases, cathepsins S and K, in the neointima of balloon-injured rat carotid arteries. , 2004, The American journal of pathology.

[9]  P. Kovanen,et al.  Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells. , 2003, Biochemical and biophysical research communications.

[10]  J. Michel.  Anoikis in the cardiovascular system: known and unknown extracellular mediators. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[11]  A. Porter,et al.  Critical role for cathepsin B in mediating caspase-1-dependent interleukin-18 maturation and caspase-1-independent necrosis triggered by the microbial toxin nigericin , 2003, Cell Death and Differentiation.

[12]  G. Taraboletti,et al.  Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. , 2003, Cancer research.

[13]  H. Du,et al.  Lysosomal Enzymes Are Released From Cultured Human Macrophages, Hydrolyze LDL In Vitro, and Are Present Extracellularly in Human Atherosclerotic Lesions , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[14]  G. Camejo.  Hydrolytic enzymes released from resident macrophages and located in the intima extracellular matrix as agents that modify retained apolipoprotein B lipoproteins. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[15]  J. Michel,et al.  The FASEB Journal express article 10.1096/fj.02-0687fje. Published online May 8, 2003. Pericellular plasmin induces smooth muscle cell anoikis , 2022 .

[16]  P. Libby,et al.  Deficiency of the Cysteine Protease Cathepsin S Impairs Microvessel Growth , 2003, Circulation research.

[17]  Makoto Naito,et al.  Deficiency of cathepsin S reduces atherosclerosis in LDL receptor-deficient mice. , 2003, The Journal of clinical investigation.

[18]  S. Katsuda,et al.  Atherosclerosis and extracellular matrix. , 2003, Journal of atherosclerosis and thrombosis.

[19]  S. Mochizuki,et al.  Signaling Pathways Transduced through the Elastin Receptor Facilitate Proliferation of Arterial Smooth Muscle Cells* , 2002, The Journal of Biological Chemistry.

[20]  A. Hamsten,et al.  Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice. , 2002, The American journal of pathology.

[21]  T. V. van Berkel,et al.  Targeting of peptides to restenotic vascular smooth muscle cells using phage display in vitro and in vivo. , 2002, Biochimica et biophysica acta.

[22]  T. Yano,et al.  Changes in aspects such as the collagenous fiber density and foam cell size of atherosclerotic lesions composed of foam cells, smooth muscle cells and fibrous components in rabbits caused by all-cis-5, 8, 11, 14, 17-icosapentaenoic acid. , 2002, Journal of atherosclerosis and thrombosis.

[23]  L. Santambrogio,et al.  IFN Regulatory Factor-1 Regulates IFN-γ-Dependent Cathepsin S Expression1 , 2002, The Journal of Immunology.

[24]  T. V. van Berkel,et al.  Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E−/− Mice After Adenovirus-Mediated Transfer of p53 , 2002, Circulation.

[25]  W. Fung-Leung,et al.  Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[26]  H. Tsuge,et al.  Structure-based design of specific cathepsin inhibitors and their application to protection of bone metastases of cancer cells. , 2002, Archives of biochemistry and biophysics.

[27]  L. Santambrogio,et al.  IFN regulatory factor-1 regulates IFN-gamma-dependent cathepsin S expression. , 2002, Journal of immunology.

[28]  M. Shilova.  Specific Features of the Spread of Tuberculosis in Russia at the End of the 20th Century , 2001, Annals of the New York Academy of Sciences.

[29]  A. Luttun,et al.  Genetic Studies on the Role of Proteinases and Growth Factors in Atherosclerosis and Aneurysm Formation , 2001, Annals of the New York Academy of Sciences.

[30]  R. Locksley,et al.  Regulation of CD1 function and NK1.1(+) T cell selection and maturation by cathepsin S. , 2001, Immunity.

[31]  P. M. Yao,et al.  Free Cholesterol Loading of Macrophages Is Associated with Widespread Mitochondrial Dysfunction and Activation of the Mitochondrial Apoptosis Pathway* , 2001, The Journal of Biological Chemistry.

[32]  J. Eaton,et al.  Apoptotic Death of Inflammatory Cells in Human Atheroma , 2001, Arteriosclerosis, thrombosis, and vascular biology.

[33]  M. Dake,et al.  Vascular endothelial growth factor enhances atherosclerotic plaque progression , 2001, Nature Medicine.

[34]  A. Daugherty,et al.  Exogenous interferon-γ enhances atherosclerosis in apolipoprotein E-/- mice , 2000 .

[35]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[36]  P. M. Yao,et al.  Free Cholesterol Loading of Macrophages Induces Apoptosis Involving the Fas Pathway* , 2000, The Journal of Biological Chemistry.

[37]  T. V. van Berkel,et al.  Low density lipoprotein receptor of macrophages facilitates atherosclerotic lesion formation in C57Bl/6 mice. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[38]  H. Ploegh,et al.  Role for Cathepsin F in Invariant Chain Processing and Major Histocompatibility Complex Class II Peptide Loading by Macrophages , 2000, The Journal of experimental medicine.

[39]  Interferon-γ elicits arteriosclerosis in the absence of leukocytes , 2000, Nature.

[40]  J. Pober,et al.  Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. , 2000, Nature.

[41]  A. Daugherty,et al.  Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/- mice. , 2000, The American journal of pathology.

[42]  P. Groot,et al.  Low Density Lipoprotein Receptor of Macrophages Facilitates Atherosclerotic Lesion Formation in C 57 Bl / 6 Mice , 2000 .

[43]  Hidde L. Ploegh,et al.  Cathepsin S Controls the Trafficking and Maturation of Mhc Class II Molecules in Dendritic Cells , 1999, The Journal of cell biology.

[44]  G. Dranoff,et al.  Cathepsin S required for normal MHC class II peptide loading and germinal center development. , 1999, Immunity.

[45]  M. Kockx.  Apoptosis in the atherosclerotic plaque: quantitative and qualitative aspects. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[46]  P. Libby,et al.  Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. , 1998, The Journal of clinical investigation.

[47]  R. Mitchell,et al.  Cathepsin S activity regulates antigen presentation and immunity. , 1998, The Journal of clinical investigation.

[48]  Y. Usson,et al.  Nuclear and cytoplasmic free calcium level changes induced by elastin peptides in human endothelial cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[49]  A. Olsson,et al.  Uptake of oxidized LDL by macrophages results in partial lysosomal enzyme inactivation and relocation. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[50]  J. Powell,et al.  Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[51]  R. Hammer,et al.  Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. , 1993, The Journal of clinical investigation.