Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells

Liu, Jian; Sukhova, Galina K.; Jin, Yang; Sun, Jiusong; Ma, Likun; An, Ruihua; Xu, Wei; Fu, Huanxiang; Dolganov, Gregory; Hu, Chengcheng; Libby, Peter; Shi, Guo Ping

doi:10.1016/j.atherosclerosis.2005.05.012

Cited by 191 publications

(213 citation statements)

References 33 publications

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“…It has recently been reported that atherosclerotic lesions in both humans and mice are associated with the expression of several lysosomal proteases, including cathepsins B, D, L and S, which may affect plaque development and stability. Oxidized low-density lipoprotein may favor LMP, inducing the death of phagocytic cells, as this has been shown in cultured cells (Li and Yuan, 2004;Liu et al, 2004a). In vivo knockout studies revealed that the deficiency of cathepsin K or S attenuates atherosclerosis (Sukhova et al, 2003).…”

Section: Lmp During Development and Aging Or Other Diseasesmentioning

confidence: 89%

“…Atherosclerosis is an inflammatory disease characterized by extensive remodeling of the extracellular matrix (Liu et al, 2004a). It has recently been reported that atherosclerotic lesions in both humans and mice are associated with the expression of several lysosomal proteases, including cathepsins B, D, L and S, which may affect plaque development and stability.…”

Section: Lmp During Development and Aging Or Other Diseasesmentioning

confidence: 99%

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Lysosomal membrane permeabilization in cell death

2008

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Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.

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Section: Lmp During Development and Aging Or Other Diseasesmentioning

confidence: 89%

Section: Lmp During Development and Aging Or Other Diseasesmentioning

confidence: 99%

Lysosomal membrane permeabilization in cell death

2008

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“…Several reports indicate expression of MMP as well as cysteine collagenases in AAA on an individual basis, [21][22][23][24][25][26] but these studies 15 are not quantitative and do not address the important posttranslational regulation of protease activity, which involves controlled activation of the inactive proenzyme and subsequent inactivation by specific and nonspecific endogenous inhibitors. 16,27 Moreover, the possible involvement of increased collagenase activity 13,14 as the underlying cause of rupture has not been addressed in detail.…”

Section: Discussionmentioning

confidence: 99%

Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

163

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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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“…Among them, cathepsin L (CatL) 3 is one of the most potent collagenases and elastases cleaving mature insoluble elastin (3). 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).…”

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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Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cells

Cited by 191 publications

References 33 publications

Lysosomal membrane permeabilization in cell death

Lysosomal membrane permeabilization in cell death

Collagen Degradation in the Abdominal Aneurysm

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

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