Endo-PDI is required for TNF alpha-induced angioge... - BV FAPESP
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Endo-PDI is required for TNF alpha-induced angiogenesis

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Autor(es):
Camargo, Livia de Lucca [1, 2] ; Babelova, Andrea [2] ; Mieth, Anja [2] ; Weigert, Andreas [3] ; Mooz, Juliane [4] ; Rajalingam, Krishnaraj [4] ; Heide, Heinrich [5] ; Wittig, Ilka [5] ; Lopes, Lucia Rossetti [1] ; Brandes, Ralf P. [2]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Sao Paulo - Brazil
[2] Goethe Univ, Inst Kardiovask Physiol, D-60590 Frankfurt - Germany
[3] Goethe Univ, Inst Biochem 1, D-60590 Frankfurt - Germany
[4] Goethe Univ, Inst Biochem 2, D-60590 Frankfurt - Germany
[5] Goethe Univ, SFB815 Core Unit, D-60590 Frankfurt - Germany
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: Free Radical Biology and Medicine; v. 65, p. 1398-1407, DEC 2013.
Citações Web of Science: 16
Resumo

Protein disulfide isomerase (PDI) and its homologs are oxidoreductases facilitating protein folding in the ER. Endo-PDI (also termed ERp46) is highly expressed in endothelial cells. It belongs to the PDI family but its physiological function is largely unknown. We studied the role of Endo-PDI in endothelial angiogenic responses. Stimulation of human umbilical vein endothelial cells (with TNF alpha (10 ng/ml) increased ERK1/ 2 phosphorylation. This effect was largely attenuated by Endo-PDI siRNA, whereas JNK and p38 MAP kinase phosphorylation was Endo-PDI independent. Similarly, TNF alpha-stimulated NF-kappa B signaling determined by 1 kappa B alpha degradation as well as TNF alpha-induced ICAM expression was unaffected by Endo-PDI siRNA. The action of Endo-PDI was not mediated by extracellular thiol exchange or cell surface PDI as demonstrated by nonpermeative inhibitors and PDI-neutralizing antibody. Moreover, exogenously added PDI failed to restore ERK1/2 activation after Endo-PDI knockdown. This suggests that Endo-PDI acts intracellularly potentially by maintaining the Ras/Raf/MEK/ERK pathway. Indeed, knockdown of Endo-PDI! attenuated Ras activation measured by G-LISA and Raf phosphorylation. ERR activation influences gene expression by the transcriptional factor AP-1, which controls MMP-9 and cathepsin B, two proteases required for angiogenesis. TNFa-stimulated MMP-9 and cathepsin B induction was reduced by silencing of Endo-PDI. Accordingly, inhibition of cathepsin B or Endo-PDI siRNA blocked the TNFa-stimulated angiogenic response in the spheroid outgrowth assays. Moreover ex vivo tube formation and in vivo Matrigel angiogenesis in response to TNFa were attenuated by Endo-PDI siRNA. In conclusion, our study establishes Endo-PDI as a novel, important mediator of AP-1-driven gene expression and endothelial angiogenic function. (C) 2013 Elsevier Inc. All rights reserved. (AU)

Processo FAPESP: 13/03520-5 - Papel da proteína dissulfeto isomerase na geração de espécies reativas de oxigênio pela NADPH oxidase durante o desenvolvimento da hipertensão arterial
Beneficiário:Lucia Rossetti Lopes
Modalidade de apoio: Auxílio à Pesquisa - Regular