Deficiency of cathepsin S reduces atherosclerosis in LDL receptor–deficient mice

Sukhova, Galina K.; Zhang, Yaou; Pan, Jie Hong; Wada, Youichiro; Yamamoto, Takashi; Naito, Makoto; Kodama, Tatsuhiko; Tsimikas, Sotirios; Witztum, Joseph L.; Lu, Michael L.; Sakara, Yasuhiko; Chin, Michael T.; Libby, Peter; Shi, Guo Ping

doi:10.1172/jci14915

Cited by 213 publications

(315 citation statements)

References 54 publications

(30 reference statements)

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“…Mice deficient in cathepsin S in LDL receptor-null mice show decreased IEL fragmentation and reduction in atherosclerosis. 26 Cystatin C deficiency in apoE-null mice resulted in increased elastic lamina fragmentation and collagen content, which could have contributed to the dilation of thoracic and abdominal aortas. 27 It remains controversial whether cystatin C deficiency affects atherosclerosis.…”

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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Section: Discussionmentioning

confidence: 99%

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Platt

Ankeny

2006

Vascular Pharmacology

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“…systems might also contribute to atherogenesis 6,24 and vascular remodeling. [12][13][14][15] We believe that our experiments represent the first characterization of the expression of elastolytic cathepsins and their inhibitor in the rat carotid artery balloon-injury model.…”

Section: Discussionmentioning

confidence: 99%

“…6,22,23 More interestingly, it has recently been reported that deficiency of cathepsin S reduced athrosclerosis in low-density lipoprotein receptor-deficient mice. 24 However, the expression of these cathepsins during neointima formation remains unknown. The expression and activity of cathepsins are tightly controlled at several levels.…”

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confidence: 99%

Increased Expression of Elastolytic Cysteine Proteases, Cathepsins S and K, in the Neointima of Balloon-Injured Rat Carotid Arteries

Cheng

Kuzuya

Sasaki

et al. 2004

The American Journal of Pathology

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The matrix-degrading activity of several proteases are involved in the accelerated breakdown of extracellular matrix associated with vascular remodeling during the development of atherosclerosis and vascular injury-induced neointimal formation. Previous studies have shown that the potent elastolytic cysteine proteases, cathepsins S and K, are overexpressed in atherosclerotic lesions in human and animal models. However, the role of these cathepsins in vascular remodeling remains unclear. In the present study, the expressions of cathepsin S and K and their inhibitor cystatin C were examined during arterial remodeling using a rat carotid artery balloon-injury model. The increase in both cathepsin S and K mRNA levels was observed from day 1 and day 3 through day 14 following the induction of balloon injury, respectively. Western blotting analysis revealed that both cathepsin S and K protein levels also increased in the carotid arteries during neointima formation, coinciding with an increase elastolytic activity assayed using Elastin-Congo red, whereas, no significant change in the expressions of cystatin C mRNA and protein was observed during follow-up periods after injury. Immunohistochemistry, Western blot, and in situ hybridization showed that the increase of cathepins S and K and the decrease of cystatin C occurred preferentially in the developing neointima. These findings suggest that cathepsin S and K may participate in the pathological arterial remodeling associated with restenosis.

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“…Although most are rapidly inactivated at the neutral pH found in the extracellular space, cathepsin S maintains 64% of its peak activity at pH 7.5 [20]. Cathepsin S RNA is increased in atherosclerotic lesions in mice [21] and its deficiency reduced elastin fiber fragmentation in hypercholesterolemic mice [22]. Cystatin C is a cathepsin inhibitor, and its mRNA is reduced in human aortic aneurisms, and its deficiency increases elastin fragmentation in hypercholesterolemic mice [11].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

Tittiger

Knutsen

et al. 2008

Molecular Genetics and Metabolism

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Mucopolysaccharidosis I (MPS I), known as Hurler syndrome in the severe form, is a lysosomal storage disease due to -L-iduronidase (IDUA) deficiency. It results in fragmentation of elastin fibers in the aorta and heart valves via mechanisms that are unclear, but may result from the accumulation of the glycosaminoglycans heparan and dermatan sulfate. Elastin fragmentation causes aortic dilatation and valvular insufficiency, which can result in cardiovascular disease. The pathophysiology of aortic disease was evaluated in MPS I mice. MPS I mice have normal elastic fiber structure and aortic compliance at early ages, which suggests that elastin assembly is normal. Elastin fragmentation and aortic dilatation are severe at 6 months, which is temporally associated with marked increases in mRNA and enzyme activity for two elastin-degrading proteins, matrix metalloproteinase-12 (MMP-12) and cathepsin S. Upregulation of these genes likely involves activation of STAT proteins, which may be induced by structural stress to smooth muscle cells from accumulation of glycosaminoglycans in lysosomes. Neonatal intravenous injection of a retroviral vector normalized MMP-12 and cathepsin S mRNA levels and prevented aortic disease. We conclude that aortic dilatation in MPS I mice is likely due to degradation of elastin by MMP-12 and/or cathepsin S. This aspect of disease might be ameliorated by inhibition of the signal transduction pathways that upregulate expression of elastase proteins, or by inhibition of elastase activity. This could result in a treatment for patients with MPS I, and might reduce aortic aneurism formation in other disorders.

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Deficiency of cathepsin S reduces atherosclerosis in LDL receptor–deficient mice

Cited by 213 publications

References 54 publications

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Laminar shear stress inhibits cathepsin L activity in endothelial cells

Increased Expression of Elastolytic Cysteine Proteases, Cathepsins S and K, in the Neointima of Balloon-Injured Rat Carotid Arteries

Upregulation of elastase proteins results in aortic dilatation in mucopolysaccharidosis I mice

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