Cathepsin L is required for endothelial progenitor cell–induced neovascularization

Urbich, Carmen; Heeschen, Christopher; Aicher, Alexandra; Sasaki, Ken-ichiro; Brühl, Thomas; Farhadi, Mohammad; Vajkoczy, Peter; Hofmann, Wolf Karsten; Peters, Christoph; Pennacchio, Len A.; Abolmaali, Nasreddin; Chavakis, Emmanouil; Reinheckel, Thomas; Zeiher, Andreas M.; Dimmeler, Stefanie

doi:10.1038/nm1182

Cited by 268 publications

(243 citation statements)

References 42 publications

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“…We validated Western blot analysis as a means of quantifying protease inhibitor complexes and found abundant expression of the active 28-kd MMP-8 form in growing and ruptured AAA, thus showing that Although the MMP-collagenases are referred to as the classic collagenases, it is now apparent that selected members of the cysteine family of proteases are involved in remodeling of the collagen matrix as well. 30 Extracellular activities of cathepsin K and L have been recognized as critical factors in bone turnover 31 and endothelial stem cell trafficking, 32 and evidence from animal studies identifies cathepsin K and S as critical factors in remodeling of the atherosclerotic plaque. 33 Sharply increased C-telopeptide fragments (CrossLaps ELISA) in aortic wall samples of AAA and an even further increase in ruptured AAA show that the cysteine proteases are also involved in collagen degradation in growing and ruptured AAA.…”

Section: Discussionmentioning

confidence: 99%

Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

164

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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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Section: Discussionmentioning

confidence: 99%

Collagen Degradation in the Abdominal Aneurysm

Abdul-Hussien

Soekhoe

Weber

et al. 2007

The American Journal of Pathology

164

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“…Notably, caveolin expression on BM cells is upregulated after ischemia, resulting in a transient CXCR4 sequestration and SDF-1-induced BM cell mobilization [38]. Activation of osteoclasts and cathepsins has also been implicated in the mobilization of the hematopoietic and endothelial progenitor cells [39,40]. Finally, additional molecules such as extracellular matrix (ECM) compounds, matrix degradation products and activated complement proteins have crucial roles in priming CXCR4 + cells and modulating the amplitude of SDF-1 signals [41][42][43].…”

Section: How Does Activation Of the Sdf-1-cxcr4 Pathway Support Mobilmentioning

confidence: 99%

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Petit

Jin

Rafii

2007

Trends in Immunology

527

382

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Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4 + BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4 + VEGFR1 + hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.

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“…The activators assayed were b-mercaptoethanol and cysteine (5,10,15,20,30 and 50 mM final concentration). The activity was compared with the enzyme without the addition of inhibitors or activators.…”

Section: Effect Of Activatorsmentioning

confidence: 99%

Granulosain I, a Cysteine Protease Isolated from Ripe Fruits of Solanum granuloso -leprosum (Solanaceae)

et al. 2008

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A new cysteine peptidase (Granulosain I) was isolated from ripe fruits of Solanum granuloso-leprosum Dunal (Solanaceae) by means of precipitation with organic solvent and cation exchange chromatography. The enzyme showed a single band by SDS-PAGE, its molecular mass was 24,746 Da (MALDI-TOF/MS) and its isoelectric point was higher than 9.3. It showed maximum activity (more than 90%) in the pH range 7-8.6. Granulosain I was completely inhibited by E-64 and activated by the addition of cysteine or 2-mercaptoethanol, confirming its cysteinic nature. The kinetic studies carried out with PFLNA as substrate, showed an affinity (Km 0.6 mM) slightly lower than those of other known plant cysteine proteases (papain and bromelain). The N-terminal sequence of granulosain I (DRLPASVDWRGKGVLVLVKNQGQC) exhibited a close homology with other cysteine proteases belonging to the C1A family.

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Cathepsin L is required for endothelial progenitor cell–induced neovascularization

Abstract: (149 words)

Cited by 268 publications

References 42 publications

Collagen Degradation in the Abdominal Aneurysm

Collagen Degradation in the Abdominal Aneurysm

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Granulosain I, a Cysteine Protease Isolated from Ripe Fruits of Solanum granuloso -leprosum (Solanaceae)

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