title: Caspase-8 is involved in neovascularization-promoting progenitor cell functions.
abstract: 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.
  
  
  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 alpha5 and beta1 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.
  
  
  CONCLUSIONS
  In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells.
authors.affiliation: Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany.
authors.forename: Dörte
authors.initials: D
authors.lastname: Scharner
authors.forename: Lothar
authors.initials: L
authors.lastname: Rössig
authors.forename: Guillaume
authors.initials: G
authors.lastname: Carmona
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Chavakis
authors.forename: Carmen
authors.initials: C
authors.lastname: Urbich
authors.forename: Ariane
authors.initials: A
authors.lastname: Fischer
authors.forename: Tae-Bong
authors.initials: TB
authors.lastname: Kang
authors.forename: David
authors.initials: D
authors.lastname: Wallach
authors.forename: Yungping Jeffrey
authors.initials: YJ
authors.lastname: Chiang
authors.forename: Yonathan Lissanu
authors.initials: YL
authors.lastname: Deribe
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D056769:Alstrom Syndrome; D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation; D006614:Hindlimb; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology* / Q000503:physiopathology / Q000601:surgery; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D017469:Receptors, Fibronectin / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000187:drug effects / Q000201:enzymology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527276:CXCR4 protein, human; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D039564:Integrin alphaV; D019012:Integrin beta1; D009842:Oligopeptides; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D017469:Receptors, Fibronectin; C403753:benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse; D053181:Caspase 8