Differential Expression of Cysteine and Aspartic Proteases during Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice

Jormsjö, Sofia; Wuttge, Dirk M.; Sirsjö, Allan; Whatling, Carl; Hamsten, Anders; Stemme, Sten; Eriksson, Per

doi:10.1016/s0002-9440(10)64254-x

Cited by 107 publications

(105 citation statements)

References 25 publications

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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%

“…[17][18][19] Among the members of the cathepsin family, cathepsin S and K express potent elastolytic as well as collagenolytic activities. 19 -21 Although it has been demonstrated that vascular SMCs have the ability to express these cathespins, 6,22 cathepsins have received much less consideration in the involvement in the neointima formation.…”

mentioning

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.…”

mentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…CatB (4,5) and CatL (6,7) expression is enhanced in human coronary lesions, but also in human carotid lesions and abdominal aortic aneurysms (8). CatK, CatS, and CatF are also expressed in human atherosclerotic lesions (9,10), and CatB, CatD, and CatL were found in macrophage-derived foam cells in lipid-rich plaque areas (11). The pathophysiological role of Cat is underlined by the findings that deficiency of CatS and CatL in LDL receptor knock-out mice reduced atherosclerotic lesions (6,12).…”

mentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ Induces Apoptosis and Inhibits Autophagy of Human Monocyte-derived Macrophages via Induction of Cathepsin L

Mahmood

Jguirim-Souissi

Hadri

et al. 2011

Journal of Biological Chemistry

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Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) ␥, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPAR␥ might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPAR␥ activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPAR␥ by the specific agonist GW929 concentration-dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPAR␥-induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPAR␥-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPAR␥ can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis.

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“…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)(3)(4)(5) and matrix metalloproteinases (MMPs) (6 -8).…”

mentioning

confidence: 99%

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

Yasuda

Greenbaum

et al. 2004

Journal of Biological Chemistry

174

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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Differential Expression of Cysteine and Aspartic Proteases during Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice

Cited by 107 publications

References 25 publications

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

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

Peroxisome Proliferator-activated Receptor γ Induces Apoptosis and Inhibits Autophagy of Human Monocyte-derived Macrophages via Induction of Cathepsin L

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

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