Inhibition of inflammatory endothelial responses by a pathway involving caspase activation and p65 cleavage.

Suppression of NFκB activation has been involved in the elimination of survival programs during endothelial cell (EC) apoptosis. We used α-tocopheryl succinate (α-TOS) to trigger apoptosome formation and the subsequent activation of executioner caspases. The level of bcl-2 was reduced by α-TOS, and its downregulation potentiated and its overexpression suppressed pro-apoptotic effects of α-TOS, indicating a mitochondrial role in α-TOS-induced apoptosis in EC. α-TOS treatment was associated with induction of TUNEL-positive apoptosis in EC with a high but not with a low proliferation index. The use of the pan-caspase inhibitor z-VAD.fmk suggested the involvement of caspases in cleavage of p65, and in inhibition of nuclear translocation of p65 and NFκB-dependent transactivation of a gene construct encoding the green fluorescence protein elicited by TNFα in contact-arrested EC. The suppression by α-TOS of inflammatory EC responses induced by TNFα such as VCAM-1 mRNA and surface protein expression and shear-res...