Cystatin C deficiency in human atherosclerosis and aortic aneurysms

Shi, Guo‐Ping; Sukhova, Galina K.; Grubb, Anders; Ducharme, Anique; Rhode, Luis H.; Lee, Richard T.; Ridker, Paul M.; Libby, Peter; Chapman, Harold A.

doi:10.1172/jci7709

Cited by 423 publications

(431 citation statements)

References 48 publications

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“…It was postulated that these deficiencies occur at the transcriptional level and relate to transforming growth factor-␤ deficiency. 42 However, our data point to a different mechanism. Reduced protein levels, albeit similar cystatin C mRNA expression, along with the inverse relationship between tissue MMP-8 and cystatin C levels and our in vitro data showing that cystatin C is degraded by various neutrophil-derived proteases such as neutrophil elastase and MMP-8, suggest that cystatin C deficiency in AAA is secondary and may relate to cystatin C degradation by neutrophil-derived proteases.…”

Section: Discussionmentioning

confidence: 51%

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Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

167

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Growth and rupture of abdominal aortic aneurysms (AAAs) result from increased collagen turnover . Collagen turnover critically depends on specific collagenases that cleave the triple helical region of fibrillar collagen. As yet , the collagenases responsible for collagen degradation in AAAs have not been identified. Increased type I collagen degradation products confirmed collagen turnover in AAAs (median values: <1 , 43 , and 108 ng/mg protein in control , growing , and ruptured AAAs , respectively). mRNA and protein analysis identified neutrophil collagenase [matrix metalloproteinase (MMP)-8] and cysteine collagenases cathepsin K , L , and S as the principle collagenases in growing and ruptured AAAs. Except for modestly increased MMP-14 mRNA levels , collagenase expression was similar in growing and ruptured AAAs (anteriorlateral wall). Evaluation of posttranslational regulation of protease activity showed a threefold increase in MMP-8 , a fivefold increase in cathepsins K and L , and a 30-fold increase in cathepsin S activation in growing and ruptured AAAs. The presence of the osteoclastic proton pump indicated optimal conditions for extracellular cysteine protease activity. Protease inhibitor mRNA expression was similar in AAAs and controls, but AAA protein levels of cystatin C, the principle cysteine protease inhibitor, were profoundly reduced (>80%). We found indications that this secondary deficiency relates to cystatin C degradation by (neutrophil-derived) proteases. Abdominal aortic aneurysm (AAA) is a common pathology and a major cause of death because of rupture. 1,2 The hallmark pathology of AAA is a persistent proteolytic imbalance that results in excess matrix destruction and progressive weakening of the arterial wall. A number of matrix metalloproteinases (MMPs) (in particular the gelatinases MMP-2 and -9) 1,3 have been implicated as primary proteolytic culprits in the disease, but it is dubious whether these proteases are directly responsible for the weakening and ultimate failure of the aortic wall. Biomechanical studies invariably show that the mechanical stability of the arterial wall essentially relies on fibrillar collagens in media and adventitia. 4 -6 These structural collagens are highly resistant toward proteolytic degradation, and the only mammalian proteases that have been shown to cleave the native triple helical region of fibrillar collagen are the classic collagenases of the MMP family 7 [ie, MMP-1, -8, and -13 and the membrane type-1 MMP (MT-1 MMP or MMP-14 8 )], as well as selected members of the cysteine protease family (ie, cathepsin K, 9,10 L, 11 and possibly S 12 ).Several reports indicate expression of these collagenases in AAA on an individual basis, but comparative data regarding expression of the collagenases, and their possible relationship to rupture of the aneurysm, 13,14 are not available. Moreover, available studies 15 do not address the critical and complex posttranslational regulation of protease activity that involves controlled secretion of an inactive proenzyme,...

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Section: Discussionmentioning

confidence: 51%

“…Reported deficiencies in cystatin C, the principle inhibitor of extracellular cysteine protease activity 42,43 in AAA may amplify the role of the cysteine proteases. It was postulated that these deficiencies occur at the transcriptional level and relate to transforming growth factor-␤ deficiency.…”

Section: Discussionmentioning

confidence: 99%

Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

167

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“…28,29 Increased cathepsin L expression and decreased cystatin C have been found in human atherosclerotic plaques and aortic aneurysms. 10,30 The differential effects of laminar and oscillatory shear stresses on cathepsin L activity reported in this study may be a critical mechanism by which AAA occurs in regions of disturbed flow. Several human and animal studies have demonstrated that atherosclerotic lesions and aneurisms of the abdominal aorta occur in the regions where they are exposed to unstable flow conditions including flow reversal, low mean wall shear stress, and high oscillatory shear index.…”

Section: Discussionmentioning

confidence: 82%

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Platt

Ankeny

2006

Vascular Pharmacology

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Objective-The cysteine proteases, cathepsins, have been implicated in vascular remodeling and atherosclerosis, processes known to be regulated by shear stress. It is not known, however, whether shear regulates cathepsins. We examined the hypothesis that shear stress regulates cathepsin activity in endothelial cells. Methods and Results-Mouse aortic endothelial cells (MAECs) exposed to atheroprotective, unidirectional laminar shear (LS) degraded significantly less BODIPY-labeled elastin and gelatin in comparison to static and proatherogenic oscillatory shear (OS). The cathepsin inhibitor E64 also reduced this activity. Gelatin zymography showed that cathepsin activity of MAECs was blunted by LS exposure and by a cathepsin L inhibitor but not by cathepsin B and S inhibitors, whereas a cathepsin K inhibitor had a minor effect. Cathepsin L siRNA knocked down cathepsin L expression, gelatinase, and elastase activity in OS and static MAECs. A partial reduction of cathepsin B protein raised the possibility that the siRNA effect on the matrix protease activity could have been attributable to cathepsin L or B. Cathepsin B activity study using the synthetic peptide showed it was not regulated by shear. Key Words: shear stress Ⅲ cathepsin Ⅲ elastase Ⅲ gelatinase Ⅲ atherosclerosis V ascular endothelial cells are constantly exposed to fluid shear stress, the frictional force generated by blood flow over the vascular endothelium. The importance of shear stress in vascular biology and pathophysiology has been highlighted by the focal development patterns of atherosclerosis in hemodynamically defined regions. For example, the regions of branched and curved arteries exposed to disturbed flow conditions including oscillatory and low mean shear stresses (OS) correspond to atheroprone areas. In contrast, straight arteries exposed to pulsatile high levels of laminar shear stress (LS) are relatively well protected from atherosclerotic plaque development. 1 Changes in blood flow have been shown to be a critical factor inducing arterial remodeling. 1-7 Increases in arterial wall shear stress prevent vascular remodeling leading to thickening of the vascular wall and inflammation, 2 whereas decreases in arterial wall shear stress promote arterial remodeling and inflammation. 2,3 Additionally, low wall shear stress leads to degradation of the internal elastic lamina (IEL). 5 Despite these findings, the underlying mechanisms by which shear regulates proteases degrading vessel wall matrix and IEL are not well described. Although there is a report demonstrating that shear regulates matrix metalloproteases (MMPs) in endothelial cells, 8 it is not clear whether other proteases are also regulated by shear. Conclusions-TheseCathepsins are the papain family of cysteine proteases which degrade elastin in addition to collagen. 9 Unlike MMPs, the role for cathepsins in blood vessel remodeling and cardiovascular disease has been understudied until recently. Cathepsins K, L, and S, potent elastinolytic proteases, have been identified in atheroscleroti...

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“…Weiss and co-workers (15,46) have recently suggested that thiol-dependent cathepsins and the matrix metalloproteinase, matrilysin, are the major elastolytic enzymes in macrophages. Moreover, cathepsin-mediated elastolytic activities in conjunction with the down-regulation of the endogenous cathepsin inhibitor, cystatin C, in atherogenic plaques have been implicated in plaque formation and plaque rupture (47). The nature of the individual elastolytic cathepsins, however, is unclear.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin V, a Novel and Potent Elastolytic Activity Expressed in Activated Macrophages

Yasuda

Greenbaum

et al. 2004

Journal of Biological Chemistry

176

138

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Atherosclerosis is characterized by a thickening and loss of elasticity of the arterial wall. Loss of elasticity has been attributed to the degradation of the arterial elastin matrix. Cathepsins K and S are papain-like cysteine proteases with known elastolytic activities, and both enzymes have been identified in macrophages present in plaque areas of diseased blood vessels. Here we demonstrate that macrophages express a third elastolytic cysteine protease, cathepsin V, which exhibits the most potent elastase activity yet described among human proteases and that cathepsin V is present in atherosclerotic plaque specimens. Approximately 60% of the total elastolytic activity of macrophages can be attributed to cysteine proteases with cathepsins V, K, and S contributing equally. From this 60%, two-thirds occur extracellularly and one-third intracellularly with the latter credited to cathepsin V. Ubiquitously expressed glycosaminoglycans (GAGs) such as chondroitin sulfate specifically inhibit the elastolytic activities of cathepsins V and K via the formation of specific cathepsin-GAG complexes. In contrast, cathepsin S, which does not form complexes with chondroitin sulfate is not inhibited; thus suggesting a specific regulation of elastolytic activities of cathepsins by GAGs. Because the GAG content is reduced in atherosclerotic plaques, an increase of cathepsins V and K activities may accelerate the destruction of the elastin matrix in diseased arteries.Atherosclerosis is characterized by arterial intimal enlargement and subsequent lipid deposition leading to the formation of blood stream obstructing plaques. The infiltration of monocyte-derived macrophages (MDMs) 1 and smooth muscle cells (SMCs) into the intima of the inflamed artery contributes to the formation of atherosclerotic lesions. Atherosclerotic lesions resident MDMs and SMCs produce a large number of extracellular matrix-degrading enzymes (1), such as cysteine proteases (2-5) and matrix metalloproteinases (MMPs) (6 -8).Elastin and collagen are the two major extracellular matrix components that provide elasticity and tensile strength to the arterial wall. The destruction of elastin and collagen causes a weakening and rupture of blood vessels (9, 10). MMPs, serine, and cysteine proteases have been identified as major elastolytic proteases in arteries (11, 12). Among cysteine proteases, cathepsins S and K have been considered as the most potent elastolytic activities with cathepsin K exhibiting a slightly higher activity than cathepsin S (13, 14). However, cathepsin K-deficient human macrophages derived from patients with pycnodysostosis were shown to retain their high cysteine proteasedependent elastolytic activities (15). This finding implied that additional cathepsins may contribute to the overall elastolytic activity in human macrophages.We and others (16 -18) have identified and partially characterized a novel human cysteine protease closely related to cathepsin L that was named cathepsin V (also known as cathepsin L2). Cathepsin V shares 80% protein s...

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Cystatin C deficiency in human atherosclerosis and aortic aneurysms

Cited by 423 publications

References 48 publications

Collagen Degradation in the Abdominal Aneurysm

Collagen Degradation in the Abdominal Aneurysm

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Cathepsin V, a Novel and Potent Elastolytic Activity Expressed in Activated Macrophages

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