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Title 

Enhancement of TNF-α-mediated cell death in vascular smooth muscle cells through cytochrome c-independent pathway by the proteasome inhibitor

Authors 

H H KimKoan Hoi Kim

Publisher 

Elsevier

Issue Date 

2003

Citation 

FEBS Letters, vol. 535, no. 1, pp. 190-194

Keywords 

atherosclerosisproteasometumor necrosis factorvascular smooth muscle cellascorbic acidbenzyloxycarbonylaspartylglutamylvalylaspartyl fluoromethyl ketonebenzyloxycarbonylleucylleucylleucinalcaspase 3caspase 3 inhibitorcaspase 8

Abstract 

There is substantial evidence that cytokines induce apoptosis of vascular smooth muscle cells (VSMCs) in atherosclerosis. Its regulation, however, is not completely defined. The aim of this study is to investigate whether proteasome activity is related with apoptosis in VSMCs by tumor necrosis factor-α (TNF-α). Rat aorta smooth muscle cells were treated with TNF-α and proteasome inhibitor MG132 and then cell death was determined by morphology, viability, and DNA fragmentation. MG132 or TNF-α alone did not induce cell death. In contrast, co-treatment of TNF-α and proteasome inhibitor induced death and DNA degradation in VSMCs, suggesting proteasome inhibitor enhanced death activity of TNF-α. The death was not blocked by ascorbic acid but by nitric oxide synthase inhibitor NG-monomethyl-L-arginine. Both caspase-3 and -8 were activated during the death by the proteasome inhibitor and TNF-α. The death was effectively blocked by the caspase-3 inhibitor z-DEVD-fmk, suggesting a role of caspase-3 in the death. Nonetheless, there were no significant alterations in the level of Bcl-2, Bcl-XL, Bax and Bak by the proteasome inhibitor, nor any evidence of cytochrome (cyt) c release into cytosol from dying cells, suggesting that cyt c is not involved. These results suggest that proteasome inhibition potentiates TNF-mediated death in VSMCs in a cyt c-independent pathway. The present study proposes a new mechanism by which VSMCs undergo death by cytokines.

ISSN 

0014-5793

Link 

http://dx.doi.org/10.1016/S0014-5793(02)03894-2

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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