Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Caveolin-1-dependent apoptosis induced by fibrin degradation products. Blood 2009 Apr 30;113(18):4431-9

Date

12/17/2008

Pubmed ID

19074731

Pubmed Central ID

PMC2676096

DOI

10.1182/blood-2008-07-169433

Scopus ID

2-s2.0-66149083175 (requires institutional sign-in at Scopus site)   36 Citations

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.

Author List

Guo YH, Hernandez I, Isermann B, Kang TB, Medved L, Sood R, Kerschen EJ, Holyst T, Mosesson MW, Weiler H

Author

Rashmi Sood PhD Associate Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Aorta
Apoptosis
Caspase 3
Caveolin 1
Cells, Cultured
Choriocarcinoma
Endothelium, Vascular
Female
Fibrin Fibrinogen Degradation Products
Glutathione Transferase
Humans
In Situ Nick-End Labeling
Mice
Mice, Knockout
Peptide Fragments
Pregnancy
Recombinant Fusion Proteins
Trophoblasts
Umbilical Veins
Uterine Neoplasms