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

doi:10.1161/ATVBAHA.108.181578

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

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

CONCLUSIONS: 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.

Original language	English
Pages (from-to)	188-94
Number of pages	7
Journal	Arteriosclerosis, Thrombosis and Vascular Biology
Volume	29
Issue number	2
DOIs	https://doi.org/10.1161/ATVBAHA.108.181578
Publication status	Published - Feb 2009

Keywords

Animals
Aorta
Apoptosis
Atherosclerosis
Bone Marrow Transplantation
Cathepsins
Cell Movement
Cell Proliferation
Cells, Cultured
Cholesterol
Collagen
Diet, Atherogenic
Disease Models, Animal
Elastic Tissue
Extracellular Matrix
Female
Foam Cells
Leukocytes
Macrophages, Peritoneal
Mice
Mice, Knockout
Myocytes, Smooth Muscle
Necrosis
Protease Inhibitors
Receptors, LDL
Transplantation Chimera

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de Nooijer, R., Bot, I., von der Thüsen, J. H., Leeuwenburgh, M. A., Overkleeft, H. S., Kraaijeveld, A. O., Dorland, R., van Santbrink, P. J., van Heiningen, S. H., Westra, M. M., Kovanen, P. T., Jukema, J. W., van der Wall, E. E., van Berkel, T. J. C., Shi, G. P., & Biessen, E. A. L. (2009). Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis. Arteriosclerosis, Thrombosis and Vascular Biology, 29(2), 188-94. https://doi.org/10.1161/ATVBAHA.108.181578

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title = "Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis",

abstract = "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.CONCLUSIONS: 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.",

keywords = "Animals, Aorta, Apoptosis, Atherosclerosis, Bone Marrow Transplantation, Cathepsins, Cell Movement, Cell Proliferation, Cells, Cultured, Cholesterol, Collagen, Diet, Atherogenic, Disease Models, Animal, Elastic Tissue, Extracellular Matrix, Female, Foam Cells, Leukocytes, Macrophages, Peritoneal, Mice, Mice, Knockout, Myocytes, Smooth Muscle, Necrosis, Protease Inhibitors, Receptors, LDL, Transplantation Chimera",

author = "\{de Nooijer\}, R and I Bot and \{von der Th{\"u}sen\}, \{J H\} and Leeuwenburgh, \{M A\} and Overkleeft, \{H S\} and Kraaijeveld, \{A O\} and R Dorland and \{van Santbrink\}, \{P J\} and \{van Heiningen\}, \{S H\} and Westra, \{M M\} and Kovanen, \{P T\} and Jukema, \{J W\} and \{van der Wall\}, \{E E\} and \{van Berkel\}, \{Th J C\} and Shi, \{G P\} and Biessen, \{E A L\}",

year = "2009",

month = feb,

doi = "10.1161/ATVBAHA.108.181578",

language = "English",

volume = "29",

pages = "188--94",

journal = "Arteriosclerosis, Thrombosis and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams \& Wilkins",

number = "2",

}

de Nooijer, R, Bot, I, von der Thüsen, JH, Leeuwenburgh, MA, Overkleeft, HS, Kraaijeveld, AO, Dorland, R, van Santbrink, PJ, van Heiningen, SH, Westra, MM, Kovanen, PT, Jukema, JW, van der Wall, EE, van Berkel, TJC, Shi, GP & Biessen, EAL 2009, 'Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis', Arteriosclerosis, Thrombosis and Vascular Biology, vol. 29, no. 2, pp. 188-94. https://doi.org/10.1161/ATVBAHA.108.181578

TY - JOUR

T1 - Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis

AU - de Nooijer, R

AU - Bot, I

AU - von der Thüsen, J H

AU - Leeuwenburgh, M A

AU - Overkleeft, H S

AU - Kraaijeveld, A O

AU - Dorland, R

AU - van Santbrink, P J

AU - van Heiningen, S H

AU - Westra, M M

AU - Kovanen, P T

AU - Jukema, J W

AU - van der Wall, E E

AU - van Berkel, Th J C

AU - Shi, G P

AU - Biessen, E A L

PY - 2009/2

Y1 - 2009/2

N2 - 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.CONCLUSIONS: 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.

AB - 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.CONCLUSIONS: 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.

KW - Animals

KW - Aorta

KW - Apoptosis

KW - Atherosclerosis

KW - Bone Marrow Transplantation

KW - Cathepsins

KW - Cell Movement

KW - Cell Proliferation

KW - Cells, Cultured

KW - Cholesterol

KW - Collagen

KW - Diet, Atherogenic

KW - Disease Models, Animal

KW - Elastic Tissue

KW - Extracellular Matrix

KW - Female

KW - Foam Cells

KW - Leukocytes

KW - Macrophages, Peritoneal

KW - Mice

KW - Mice, Knockout

KW - Myocytes, Smooth Muscle

KW - Necrosis

KW - Protease Inhibitors

KW - Receptors, LDL

KW - Transplantation Chimera

U2 - 10.1161/ATVBAHA.108.181578

DO - 10.1161/ATVBAHA.108.181578

M3 - Article

C2 - 19095996

SN - 1079-5642

VL - 29

SP - 188

EP - 194

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

IS - 2

ER -

Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis

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Keywords

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