Cystatin C deficiency in human atherosclerosis and aortic aneurysms.
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.
Shi
G P
GP
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. guo-ping_shi@hms.harvard.edu
Sukhova
G K
GK
Grubb
A
A
Ducharme
A
A
Rhode
L H
LH
Lee
R T
RT
Ridker
P M
PM
Libby
P
P
Chapman
H A
HA
D001011:Aorta / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism* / Q000473:pathology; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D055316:Cystatin C; D015891:Cystatins / Q000097:blood / Q000172:deficiency*; D015853:Cysteine Proteinase Inhibitors / Q000097:blood / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma