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A1 functions at the mitochondria to delay endothelial apoptosis in response to tumor necrosis factor

A1 functions at the mitochondria to delay endothelial apoptosis in response to tumor necrosis factor
A1 functions at the mitochondria to delay endothelial apoptosis in response to tumor necrosis factor
Tumor necrosis factor (TNF) does not cause endothelial apoptosis unless the expression of cytoprotective genes is blocked. We have previously demonstrated that one of the TNF-inducible cytoprotective genes is the Bcl-2 family member, A1. A1 is induced by the action of the transcription factor, NFkappaB, in response to inflammatory mediators. In this report we demonstrate that, as with other cell types, inhibition of NFkappaB initiates microvascular endothelial apoptosis in response to TNF. A1 is able to inhibit this apoptosis over 24 h. We demonstrate that A1 is localized to and functions at the mitochondria. Whereas A1 is able to inhibit mitochondrial depolarization, loss of cytochrome c, cleavage of caspase 9, BID, and poly(ADP-ribose) polymerase, it does not block caspase 8 or caspase 3 cleavage. In contrast, A1 is not able to prevent endothelial apoptosis by TNF over 72 h, when NFkappaB signaling is blocked. On the other hand, the caspase inhibitor, benzyloxycarbonyl-VAD-formylmethyl ketone, completely blocks TNF-induced endothelial apoptosis over 72 h. Our findings indicate that A1 is able to maintain temporary survival of endothelial cells in response to TNF by maintaining mitochondrial viability and function. However, a mitochondria-independent caspase pathway eventually results in endothelial death despite mitochondrial protection by A1.
0021-9258
18099-18107
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Wong, Fred
f163e691-cc42-4de6-bd76-0abde9539ce8
Dorovini-Zis, Katerina
19529142-8737-4483-b468-da7b1bc92ba9
Shahidi, Reza
45eba585-2033-4ec8-9395-b9d778c55937
Karsan, Aly
4e7a164d-e912-42e1-9647-201067b473cc
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Wong, Fred
f163e691-cc42-4de6-bd76-0abde9539ce8
Dorovini-Zis, Katerina
19529142-8737-4483-b468-da7b1bc92ba9
Shahidi, Reza
45eba585-2033-4ec8-9395-b9d778c55937
Karsan, Aly
4e7a164d-e912-42e1-9647-201067b473cc

Duriez, Patrick J., Wong, Fred, Dorovini-Zis, Katerina, Shahidi, Reza and Karsan, Aly (2000) A1 functions at the mitochondria to delay endothelial apoptosis in response to tumor necrosis factor. The Journal of Biological Chemistry, 275 (24), 18099-18107. (doi:10.1074/jbc.M908925199). (PMID:10849436)

Record type: Article

Abstract

Tumor necrosis factor (TNF) does not cause endothelial apoptosis unless the expression of cytoprotective genes is blocked. We have previously demonstrated that one of the TNF-inducible cytoprotective genes is the Bcl-2 family member, A1. A1 is induced by the action of the transcription factor, NFkappaB, in response to inflammatory mediators. In this report we demonstrate that, as with other cell types, inhibition of NFkappaB initiates microvascular endothelial apoptosis in response to TNF. A1 is able to inhibit this apoptosis over 24 h. We demonstrate that A1 is localized to and functions at the mitochondria. Whereas A1 is able to inhibit mitochondrial depolarization, loss of cytochrome c, cleavage of caspase 9, BID, and poly(ADP-ribose) polymerase, it does not block caspase 8 or caspase 3 cleavage. In contrast, A1 is not able to prevent endothelial apoptosis by TNF over 72 h, when NFkappaB signaling is blocked. On the other hand, the caspase inhibitor, benzyloxycarbonyl-VAD-formylmethyl ketone, completely blocks TNF-induced endothelial apoptosis over 72 h. Our findings indicate that A1 is able to maintain temporary survival of endothelial cells in response to TNF by maintaining mitochondrial viability and function. However, a mitochondria-independent caspase pathway eventually results in endothelial death despite mitochondrial protection by A1.

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More information

Published date: 16 June 2000

Identifiers

Local EPrints ID: 164807
URI: https://eprints.soton.ac.uk/id/eprint/164807
ISSN: 0021-9258
PURE UUID: b7e3cb6f-0307-44a7-bdf1-42e3eb048c37

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Date deposited: 05 Oct 2010 09:14
Last modified: 18 Jul 2017 12:28

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