title: Caveolin-1-dependent apoptosis induced by fibrin degradation products.
abstract: In mice lacking the blood coagulation regulator thrombomodulin, fibrinolytic degradation products (FDP) of fibrin induce apoptotic cell death of a specialized cell type in the placenta, polyploid trophoblast giant cells. Here, we document that this bioactivity of FDP is conserved in human FDP, is not limited to trophoblast cells, and is associated with an Aalpha-chain segment of fibrin fragment E (FnE). The majority of proapoptotic activity is arginine-glycine-aspartic acid (RGD)-independent and requires caveolin-1-dependent cellular internalization of FnE. Internalization through caveoli is mediated by an epitope contained within Aalpha52-81 that is necessary and sufficient for cellular uptake of FnE. Aalpha52-81 does not cause apoptosis itself, and competitively inhibits FnE internalization and apoptosis induction. Apoptotic activity per se resides within Aalpha17-37 and requires the N-terminal neoepitope generated by release of fibrinopeptide A. Cellular internalization of FnE elicits depression of mitochondrial function and consequent apoptosis that is strictly dependent on the activity of caspases 9 and 3. These findings describe the molecular details of a novel mechanism linking fibrin degradation to cell death in the placenta, which may also contribute to pathologic alterations in nonplacental vascular beds that are associated with fibrinolysis.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53226-3548, USA.
authors.forename: Yi-He
authors.initials: YH
authors.lastname: Guo
authors.forename: Irene
authors.initials: I
authors.lastname: Hernandez
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Tae-bong
authors.initials: TB
authors.lastname: Kang
authors.forename: Leonid
authors.initials: L
authors.lastname: Medved
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sood
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kerschen
authors.forename: Trudy
authors.initials: T
authors.lastname: Holyst
authors.forename: Michael W
authors.initials: MW
authors.lastname: Mosesson
authors.forename: Hartmut
authors.initials: H
authors.lastname: Weiler
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D051242:Caveolin 1 / Q000502:physiology*; D002478:Cells, Cultured; D002822:Choriocarcinoma / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D011247:Pregnancy; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism; D014594:Uterine Neoplasms / Q000378:metabolism / Q000473:pathology
chemical_list: D051242:Caveolin 1; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; C072054:fibrin fragment E-2; D005982:Glutathione Transferase; D053148:Caspase 3