Journal
BIOCHEMISTRY
Volume 40, Issue 15, Pages 4686-4692Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi002498n
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Suppression of NF kappaB activation has been involved in the elimination of survival programs during endothelial cell (EC) apoptosis. We used alpha -tocopheryl succinate (alpha -TOS) to trigger apoptosome formation and the subsequent activation of executioner caspases. The level of bcl-2 was reduced by alpha -TOS, and its downregulation potentiated and its overexpression suppressed pro-apoptotic effects of alpha -TOS, indicating a mitochondrial role in alpha -TOS-induced apoptosis in Ec. alpha -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 NF kappaB-dependent transactivation of a gene construct encoding the green fluorescence protein elicited by TNF alpha in contact-arrested EC. The suppression by alpha -TOS of inflammatory EC responses induced by TNF alpha such as VCAM-1 mRNA and surface protein expression and shear-resistant arrest of monocytic cells were also reversed by z-VAD.fmk. NF kappaB-dependent transactivation was preserved in alpha -TOS-treated EC stably transfected with a caspase-noncleavable p65 mutant but not with its truncated form, thus establishing a direct link between alpha -TOS-induced effects and p65 cleavage. Our data infer a pathway by which caspase activation in EC inhibits NF kappaB-dependent inflammatory activation and monocyte recruitment, and provide evidence for a relationship between proapoptotic and anti-inflammatory pathways.
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