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Title 

Sensitization of vascular smooth muscle cell to TNF-α-mediated death in the presence of palmitate

Authors 

Mun Chual RhoK A LeeS M KimC S LeeM J JangYoung Kook KimHyun Sun LeeY H ChoiB Y RhimK Kim

Publisher 

Elsevier

Issue Date 

2007

Citation 

Toxicology and Applied Pharmacology, vol. 220, no. 3, pp. 311-319

Keywords 

apoptosispalmitatetumor necrosis factorvascular smooth muscle cellFas associated death domain proteincell deathcell viabilityhuman cellsmooth muscle fibervascular smooth muscle

Abstract 

Saturated free fatty acids (FFAs), including palmitate, can activate the intrinsic death pathway in cells. However, the relationship between FFAs and receptor-mediated death pathway is still unknown. In this study, we have investigated whether FFAs are able to trigger receptor-mediated death. In addition, to clarify the mechanisms responsible for the activation, we examined the biochemical changes in dying vascular smooth muscle cell (VSMC) and the effects of various molecules to the receptor-mediated VSMC death. Tumor necrosis factor (TNF)-α-mediated VSMC death occurred in the presence of sub-cytotoxic concentration of palmitate as determined by assessing viability and DNA degradation, while the cytokine did not influence VSMC viability in the presence of oleate. The VSMC death was inhibited by the gene transfer of a dominant-negative Fas-associated death domain-containing protein and the baculovirus p35, but not by the bcl-xL or the c-Jun N-terminal kinase (JNK) binding domain of JNK-interacting protein-1, in tests utilizing recombinant adenoviruses. The VSMC death was also inhibited by a neutralizing anti-TNF receptor 1 antibody, the caspase inhibitor z-VAD, and the cathepsin B inhibitor CA074, a finding indicative of the role of both caspases and cathepsin B in this process. Consistent with this finding, caspase-3 activation and an increase in cytosolic cathepsin B activity were detected in the dying VSMC. Palmitate inhibited an increase of TNF-α-mediated nuclear factor kappa B (NF-κB) activity, the survival pathway activated by the cytokine, by hindering the translocation of the NF-κB subunit of p65 from the cytosol into the nucleus. The gene transfer of inhibitor of NF-κB predisposed VSMC to palmitate-induced cell death. To the best of our knowledge, this study is the first report to demonstrate the activation of TNF-α-mediated cell death in the presence of palmitate. The current study proposes that FFAs would take part in deleterious vascular consequences of such patients with elevated levels of FFAs as diabetics and obese individuals via the triggering of receptor-mediated death pathways of VSMC.

ISSN 

0041-008X

Link 

http://dx.doi.org/10.1016/j.taap.2007.02.008

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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