ROLE OF CASPASE-1 AND CASPASE-3 AND BCL-2-RELATED MOLECULES IN ENDOTHELIAL-CELL APOPTOSIS ASSOCIATED WITH THROMBOTIC MICROANGIOPATHIES

We have defined an in vitro model for the study of microvascular endot helial cell (EC) apoptosis mediated by plasma from patients with vario us forms of thrombotic thrombocytopenic purpura (TTP) and hemolytic-ur emic syndrome (HUS), This system reproduces a variety of histopatholog ic 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 abilit y of tetrapeptide-based inhibitors of interleukin 1 beta-converting en zyme (ICE)-like caspase 1 and cysteine protease protein (CPP)BS-like c aspase 3, two members of a novel class of cysteine proteases involved in final pathways to apoptosis, to block TTP/sporadic HUS plasma-media ted apoptosis, Overexpression of Bcl-X-L via gene transfer suppressed this apoptosis by 70%, Transduction of EC with the Bcl-2 homolog Al ha d 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 inhibi tors may have a role in the experimental therapeutics of these syndrom es. (C) 1998 Wiley-Liss, Inc.