Cathepsin D and Cathepsin L Activities in Aortic Aneurysm Wall and Parietal Thrombus

Gacko, Marek; Głowiński, S.

doi:10.1515/cclm.1998.075

Cited by 44 publications

(32 citation statements)

References 16 publications

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“…Of note, up-regulation of both cathepsins C and D expression and activity has been reported in aneurysms. 26 In summary, increased and differential expression of several cathepsins in atherosclerotic plaques suggests that these proteases may participate in atherogenesis and increase the risk of plaque rupture. In particular, cathepsin S expression was associated with atherosclerosis with an extensive expression in the fibrous plaque and medial SMC layer.…”

Section: Discussionmentioning

confidence: 99%

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

Jormsjö

Wuttge

Sirsjö

et al. 2002

The American Journal of Pathology

109

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Section: Discussionmentioning

confidence: 99%

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

Jormsjö

Wuttge

Sirsjö

et al. 2002

The American Journal of Pathology

109

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“…CathL and LDL receptor double-deficient mice were recently found to be protected from the development of atherosclerotic lesions, compared with LDL receptor-deficient mice, and manifested reduced medial elastin degradation (42). Protein levels and CathL activity were elevated within the vascular wall of patients with abdominal aortic aneurysm, a disease that typifies extensive ECM degradation and vascular remodeling (37,54,55).…”

Section: Discussionmentioning

confidence: 99%

Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis

Cailhier

Sirois

Laplante

et al. 2008

Journal of Biological Chemistry

121

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Proteolysis of extracellular matrix components and the production of cryptic bioactive factors play key roles in vascular remodeling. We showed previously that extracellular matrix proteolysis is triggered by the apoptosis of endothelial cells (EC), resulting in the release of an anti-apoptotic C-terminal fragment of endorepellin (LG3). Here, we characterize the endorepellin-cleaving proteases released by apoptotic EC using a multifaceted proteomics strategy. Cathepsin L (CathL), a cysteine protease known to be associated with cardiovascular disease progression in animal models and humans, was isolated from medium conditioned by apoptotic EC. CathL cleaved recombinant endorepellin in vitro, leading to LG3 release. Inhibition of CathL activity in EC exposed to pro-apoptotic stimuli prevented LG3 release without modulating the development of apoptosis in EC. Inhibition of caspase-3 activation in EC with the biochemical inhibitor DEVD-fluoromethyl ketone or small interfering RNAs concomitantly prevented CathL release by EC, LG3 production, and the development of paracrine anti-apoptotic activity. These data demonstrate that caspase-3 activation is a novel pathway of importance for triggering extracellular CathL release and the cleavage of extracellular matrix components. Apoptosis of endothelial cells (EC)4 is increasingly recognized as an important component of the "response to injury" process, as most clinical risk factors of atherosclerosis (such as hypertension (1, 2), hyperglycemia (3, 4), oxidized low density lipoproteins (LDLs) (5, 6) and oxidative stress (7)) induce EC apoptosis. Interventions aimed at preventing EC apoptosis in animal models of transplant vasculopathy, an immune-mediated form of atherosclerosis, prevent neointima formation, indicating that EC apoptosis is an important pro-atherosclerotic trigger (8 -13). During vascular remodeling, EC injury and apoptosis are followed by migration of ␣-smooth muscle actinpositive cells (smooth muscle cells (SMC) and myofibroblasts) that accumulate within the intima through a state of resistance to apoptosis largely dependent on Bcl-xl overexpression (14 -16).Recent evidence from our group and others suggests that apoptotic EC favor neointima formation through the release of paracrine mediators, which in turn, increase Bcl-xl expression and inhibit the apoptosis of vascular SMC and fibroblasts (17)(18)(19)(20). The production of biologically active mediators by apoptotic EC is at least partially dependent on pericellular proteolysis, leading to basement membrane and extracellular matrix (ECM) degradation with the release of cryptic anti-apoptotic factors (18 -20). A C-terminal fragment of endorepellin (perlecan domain V) released in association with EC apoptosis was found to heighten Bcl-xl expression in SMC and fibroblasts (18 -20). Perlecan is a basement membrane modular proteoglycan composed of five structural domains (21). The C-terminal domain, also called endorepellin, comprises three laminin-like globular (LG1-LG3) modules interspaced by four epiderm...

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“…Cathepsin D, the increased expression of which in atherosclerosis and aneurysm tissue has been well described, is a cysteine protease. 7,20,21) Apoptosis and inflammation: It is known that apoptosis of vascular smooth muscle cells is increased within the medial layer of aneurysmal aortic tissue. 13) In our microarray assays, apoptosis related genes such as caspase 4 and TNF family genes were upregulated.…”

Section: Discussionmentioning

confidence: 99%

Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms: Microarray Analysis of Surgically Resected Specimens

et al. 2005

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SUMMARYChanges in the expression levels of several genes have been described in aortic aneurysm specimens, however, the spectrum of diverse molecular alterations remains to be elucidated. We attempted to identify key molecules that modulate the pathogenesis of aortic aneurysm, using a complimentary DNA microarray carrying approximately 13,000 human genes.Segments of thoracic aortic aneurysms (TAA) and adjacent normal thoracic aortic tissues without aneurysmal changes (NTA) were obtained from 20 patients undergoing graft surgery. RNA obtained from five pairs of TAA and NTA samples was compared to determine aneurysm-specific alterations using microarray. Further, the expression levels of several genes of interest were verified in the remaining specimens by real-time reverse transcription-polymerase chain reaction (RT-PCR).In microarray assays, several types of the matrix metalloproteinases were upregulated as reported previously. Also, 220 genes suggested to be involved in protein degradation, inflammation, apoptosis, stress response, intracellular signaling, and other processes were significantly upregulated. Many of these genes have not been previously implicated in cardiovascular disease. The real time RT-PCR independently confirmed that the expression levels of MMP-2, MMP-9, ADAMTS-1, and caspase 4 were consistently increased in TAA.The results indicate that many genes are involved in a complicated manner in the pathogenesis of TAA. Investigation of these genes will help clarify the pathogenesis of this disease, and may lead to the discovery of novel therapeutic targets. (Int Heart J 2005; 46: 265-277)

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Cathepsin D and Cathepsin L Activities in Aortic Aneurysm Wall and Parietal Thrombus

Cited by 44 publications

References 16 publications

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

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

Caspase-3 Activation Triggers Extracellular Cathepsin L Release and Endorepellin Proteolysis

Altered Patterns of Gene Expression Specific to Thoracic Aortic Aneurysms: Microarray Analysis of Surgically Resected Specimens

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