Deficiency of the Cysteine Protease Cathepsin S Impairs Microvessel Growth

Shi, Guo Ping; Sukhova, Galina K.; Kuzuya, Masafumi; Ye, Q.; Du, Jie; Zhang, Y.; Pan, Jiehong; Lu, Michael L.; Cheng, Xianwu; Iguchi, Akihisa; Perrey, S.; Lee, A.M.-E.; Chapman, Harold A.; Libby, Peter

doi:10.1161/01.res.0000060485.20318.96

Cited by 197 publications

(169 citation statements)

References 27 publications

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“…Moreover, pharmacological inhibition and siRNA interference of CathK impaired EC migration/invasion, proliferation and tubule formation. Among Cat family members, CatS and CatL were shown to contribute to angiogenesis 4,12 . However, the pharmacological inhibition of these Cats did not affect the migration or proliferation of mature ECs or vascular smooth muscle cells 12,15 .…”

Section: Discussionmentioning

confidence: 99%

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Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

et al. 2014

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Section: Discussionmentioning

confidence: 99%

“…It is well known that matrix metalloproteinases (MMPs) and serine proteases have essential roles in these processes 2,3 . However, recent evidence shows that other proteolytic pathways, such as the cysteine protease cathepsin (Cat) family, are also involved in angiogenesis 4,5 .…”

mentioning

confidence: 99%

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

et al. 2014

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“…3 Although the mechanisms controlling cathepsin activities in smooth muscle cells 11 and macrophages 22,39,40 have been reported, the role of cathepsins in endothelial cells have been rather limited. Shi et al showed that cathepsin S deficiency led to abnormal angiogenic responses attributable to abnormal extracellular matrix degradation.…”

Section: Discussionmentioning

confidence: 99%

“…Shi et al showed that cathepsin S deficiency led to abnormal angiogenic responses attributable to abnormal extracellular matrix degradation. 40 Also, cathepsin L has been shown to play an important role in endothelial progenitor cell-mediated neovascularization. 38 Although shear stress has been shown to increase cathepsin B activity in neutrophils, 41 the current study is the first report showing that cathepsins are regulated by shear stress in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

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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“…The abnormal angiogenesis in micro-vascular endothelial cells and defective micro-vessel development during wound repair occurred in Cat S deficient mice. These indicated that Cat S plays an important role in aspects of angiogenesis both in vitro and in vivo 3 . Furthermore, high Cat S expression has also been observed in a range of tumors such as prostate, astrocytomas, hepatocellular and pancreatic carcinomas [4][5][6][7] .…”

Section: Introductionmentioning

confidence: 93%

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

Tsai

Lee

Chang

et al. 2013

Journal of Enzyme Inhibition and Medicinal Chemistry

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Elevated cathepsin S (Cat S) level is correlated with higher migration ability in tumor cells. This study investigates the inhibitory effect of novel synthetic a-ketoamide compounds on cathepsin activity and cancer cell migration. The effect of several a-ketoamide compounds on the activity of recombinant cathepsins (Cat S, Cat L and Cat K) was examined. Two highly metastatic cancer cell lines were incubated with three Cat S-specific compounds (6n, 6w and 6r) to analyze their effect on cellular Cat S activity and cell migration. At a 100 nM concentration, compounds 6n, 6r and 6w effectively inhibited Cat S activity. Cat S activity and cell migration were significantly reduced in CL1-3 cells after treatment with either 6n or 6w at 5 mM. Similar results were also obtained when A2058 cells were treated with 6n. These results highlight the therapeutic potential of a-ketoamide compounds, especially 6n and 6w, to prevent or delay cancer metastasis.

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Deficiency of the Cysteine Protease Cathepsin S Impairs Microvessel Growth

Cited by 197 publications

References 27 publications

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Effects of novel human cathepsin S inhibitors on cell migration in human cancer cells

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