TY - JOUR
T1 - Caspase-8 is involved in neovascularization-promoting progenitor cell functions
AU - Scharner, Dörte
AU - Rössig, Lothar
AU - Carmona, Guillaume
AU - Chavakis, Emmanouil
AU - Urbich, Carmen
AU - Fischer, Ariane
AU - Kang, Tae Bong
AU - Wallach, David
AU - Chiang, Yungping Jeffrey
AU - Deribe, Yonathan Lissanu
AU - Dikic, Ivan
AU - Zeiher, Andreas M.
AU - Dimmeler, Stefanie
N1 - Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/4/1
Y1 - 2009/4/1
N2 - OBJECTIVE: Endothelial progenitor cells (EPCs) comprise a heterogeneous population of cells, which improve therapeutic neovascularization after ischemia. The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Caspases mediate apoptosis but are also involved in other critical biological processes. Therefore, we aimed to address the role of caspases in proangiogenic cells. METHODS AND RESULTS: The caspase-8 inhibitor zIETD abrogated the ex vivo formation of EPCs, inhibited EPC adhesion and migration, and reduced their capacity to improve neovascularization in vivo. Consistently, cells isolated from caspase-8-deficient mice exhibited a reduced capacity for enhancing neovascularization when transplanted into mice after hindlimb ischemia. Because inhibition of Caspase-8 reduced the adhesion and homing functions of EPCs, we further determined the surface expression of integrins and receptors involved in cell recruitment to ischemic tissues. Pharmacological inhibition of caspase-8 and genetic depletion of caspase-8 reduced the expression of the fibronectin receptor subunits α5 and β1 and the SDF-1 receptor CXCR4. Moreover, we identified the E3 ubiquitin ligase Cbl-b, which negatively regulates integrin and receptor-mediated signaling, as a potential Caspase-8 substrate. CONCLUSION: In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
AB - OBJECTIVE: Endothelial progenitor cells (EPCs) comprise a heterogeneous population of cells, which improve therapeutic neovascularization after ischemia. The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Caspases mediate apoptosis but are also involved in other critical biological processes. Therefore, we aimed to address the role of caspases in proangiogenic cells. METHODS AND RESULTS: The caspase-8 inhibitor zIETD abrogated the ex vivo formation of EPCs, inhibited EPC adhesion and migration, and reduced their capacity to improve neovascularization in vivo. Consistently, cells isolated from caspase-8-deficient mice exhibited a reduced capacity for enhancing neovascularization when transplanted into mice after hindlimb ischemia. Because inhibition of Caspase-8 reduced the adhesion and homing functions of EPCs, we further determined the surface expression of integrins and receptors involved in cell recruitment to ischemic tissues. Pharmacological inhibition of caspase-8 and genetic depletion of caspase-8 reduced the expression of the fibronectin receptor subunits α5 and β1 and the SDF-1 receptor CXCR4. Moreover, we identified the E3 ubiquitin ligase Cbl-b, which negatively regulates integrin and receptor-mediated signaling, as a potential Caspase-8 substrate. CONCLUSION: In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
KW - Angiogenesis
KW - Cell therapy
KW - Homing
KW - Integrin
KW - Progenitor cells
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U2 - 10.1161/ATVBAHA.108.182006
DO - 10.1161/ATVBAHA.108.182006
M3 - Article
C2 - 19122169
AN - SCOPUS:63449131568
SN - 1079-5642
VL - 29
SP - 571
EP - 578
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 4
ER -