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Cystatin C deficiency in human atherosclerosis and aortic aneurysms

Shi, Guo-Ping ; Sukhova, Galina K. ; Grubb, Anders LU orcid ; Ducharme, Anique ; Rhode, Luis H. ; Lee, Richard T. ; Ridker, Paul M. ; Libby, Peter and Chapman, Harold A. (1999) In Journal of Clinical Investigation 104(9). p.1191-1197
Abstract

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose... (More)

The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-beta(1). The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease.

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; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aorta/pathology, Aortic Aneurysm, Abdominal/metabolism, Arteries/metabolism, Arteriosclerosis/metabolism, Cells, Cultured, Cystatin C, Cystatins/blood, Cysteine Proteinase Inhibitors/blood, Dose-Response Relationship, Drug, Humans, Immunoblotting, Immunohistochemistry, Interferon-gamma/metabolism, Muscle, Smooth/metabolism, Transforming Growth Factor beta/metabolism
in
Journal of Clinical Investigation
volume
104
issue
9
pages
1191 - 1197
publisher
The American Society for Clinical Investigation
external identifiers
  • scopus:0032718590
  • pmid:10545518
ISSN
0021-9738
DOI
10.1172/JCI7709
language
English
LU publication?
yes
id
fe46d46e-7ddb-489b-8597-37795162585b
date added to LUP
2021-11-02 13:27:35
date last changed
2024-11-18 12:12:48
@article{fe46d46e-7ddb-489b-8597-37795162585b,
  abstract     = {{<p>The pathogenesis of atherosclerosis and abdominal aortic aneurysm involves breakdown of the elastic laminae. Elastolytic cysteine proteases, including cathepsins S and K, are overexpressed at sites of arterial elastin damage, but whether endogenous local inhibitors counterbalance these proteases is unknown. We show here that, whereas cystatin C is normally expressed in vascular wall smooth muscle cells (SMCs), this cysteine protease inhibitor is severely reduced in both atherosclerotic and aneurysmal aortic lesions. Furthermore, increased abdominal aortic diameter among 122 patients screened by ultrasonography correlated inversely with serum cystatin C levels. In vitro, cytokine-stimulated vascular SMCs secrete cathepsins, whose elastolytic activity could be blocked when cystatin C secretion was induced by treatment with TGF-beta(1). The findings highlight a potentially important role for imbalance between cysteine proteases and cystatin C in arterial wall remodeling and establish that cystatin C deficiency occurs in vascular disease.</p>}},
  author       = {{Shi, Guo-Ping and Sukhova, Galina K. and Grubb, Anders and Ducharme, Anique and Rhode, Luis H. and Lee, Richard T. and Ridker, Paul M. and Libby, Peter and Chapman, Harold A.}},
  issn         = {{0021-9738}},
  keywords     = {{Aorta/pathology; Aortic Aneurysm, Abdominal/metabolism; Arteries/metabolism; Arteriosclerosis/metabolism; Cells, Cultured; Cystatin C; Cystatins/blood; Cysteine Proteinase Inhibitors/blood; Dose-Response Relationship, Drug; Humans; Immunoblotting; Immunohistochemistry; Interferon-gamma/metabolism; Muscle, Smooth/metabolism; Transforming Growth Factor beta/metabolism}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{1191--1197}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{Cystatin C deficiency in human atherosclerosis and aortic aneurysms}},
  url          = {{http://dx.doi.org/10.1172/JCI7709}},
  doi          = {{10.1172/JCI7709}},
  volume       = {{104}},
  year         = {{1999}},
}