title: Role of caspases 1 and 3 and Bcl-2-related molecules in endothelial cell apoptosis associated with thrombotic microangiopathies.
abstract: We have defined an in vitro model for the study of microvascular endothelial cell (EC) apoptosis mediated by plasma from patients with various forms of thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). This system reproduces a variety of histopathologic and ultrastructural features of tissue EC involved in TTP/sporadic HUS, suggesting that apoptotic EC injury is a primary pathophysiologic event in the thrombotic microangiopathies. We now document the ability of tetrapeptide-based inhibitors of interleukin 1beta-converting enzyme (ICE)-like caspase 1 and cysteine protease protein (CPP)-32-like caspase 3, two members of a novel class of cysteine proteases involved in final pathways to apoptosis, to block TTP/sporadic HUS plasma-mediated apoptosis. Overexpression of Bcl-X(L) via gene transfer suppressed this apoptosis by 70%. Transduction of EC with the Bcl-2 homolog A1 had a more limited protective effect. These findings support a role for apoptosis-linked cysteine proteases in the pathophysiology of TTP and sporadic HUS, and raise the possibility that specific apoptosis inhibitors may have a role in the experimental therapeutics of these syndromes.
authors.affiliation: Laboratory for AIDS Virus Research, Department of Medicine, Cornell University Medical College, New York, New York, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mitra
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: C
authors.initials: C
authors.lastname: MacLow
authors.forename: A
authors.initials: A
authors.lastname: Karsan
authors.forename: J
authors.initials: J
authors.lastname: Laurence
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001327:Autoimmune Diseases / Q000378:metabolism* / Q000473:pathology; D020170:Caspase 1 / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology; D006463:Hemolytic-Uremic Syndrome / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000378:metabolism* / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; D061945:Caspase Inhibitors; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1