Endothelial activation by angiotensin II through NFκB and p38 pathways

Involvement of NFκB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin

Antonio Costanzo, Francesca Moretti, Vito Lelio Burgio, Cristina Bravi, Francesco Guido, Massimo Levrero, Pier Lorenzo Puri

Research output: Contribution to journalArticle

129 Citations (Scopus)

Abstract

Angiotensin-II (AII), the dominant effector of the renin-angiotensin system, is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis. Upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin in endothelial cells by inflammatory cytokines through nuclear factor kappa B (NFκB) activation is implicated in formation and progression of atherosclerotic plaque. Here we show that AII induces NFκB-dependent transcription in primary endothelial cell lines, leading to the upregulation of ICAM-1 and VCAM-1 expression. NFκB activation by AII is mediated by the NFκB-inducing kinase (NIK), a common mediator of NFκB activation by inflammatory cytokines, such as TNF-α. However, NFκB stimulation by AII differs from that of TNF-α since a TNF-receptor associated factor 2 (TRAF-2) dominant negative mutant does not prevent AII-mediated NFκB activation. In analogy with TNF-α-dependent activation of NFκB, treatment with either the anti-oxidant N-acetyl cysteine (NAC) or the cyclooxygenase (COX) inhibitor acetyl salicylic acid (aspirin), but not indometacin, prevents the induction of NFκB-dependent transcription by AII. Thus, production of reactive oxygen species, aspirin (asp)-sensitive enzymes of the arachidonate metabolism, and NIK are common transducers of AII- and TNF-dependent pathways to NFκB. AII also activates the inflammatory p38 kinase in endothelial cells, an effect inhibited by exposure to either NAC or asp. Pharmacological interference of the p38 pathway, with the inhibitor SB 202190, prevented AII-mediated activation of the NFκB target V-CAM, without affecting degradation of IκBα. These results support a pro-inflammatory effect of the vasoactive peptide AII in endothelial cells, through at least two pathways - NFκB and p38 - both of which are sensitive to asp and antioxidants.

Original languageEnglish
Pages (from-to)402-410
Number of pages9
JournalJournal of Cellular Physiology
Volume195
Issue number3
DOIs
Publication statusPublished - Jun 1 2003

Fingerprint

NF-kappa B
Angiotensin II
Aspirin
Free Radicals
Reactive Oxygen Species
Phosphotransferases
Chemical activation
Endothelial cells
Endothelial Cells
Acetylcysteine
Vascular Cell Adhesion Molecule-1
Intercellular Adhesion Molecule-1
Transcription
Cysteine
NF-kappa B kinase
Up-Regulation
TNF Receptor-Associated Factor 2
Cytokines
E-Selectin
Salicylic Acid

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

Cite this

Endothelial activation by angiotensin II through NFκB and p38 pathways : Involvement of NFκB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin. / Costanzo, Antonio; Moretti, Francesca; Burgio, Vito Lelio; Bravi, Cristina; Guido, Francesco; Levrero, Massimo; Puri, Pier Lorenzo.

In: Journal of Cellular Physiology, Vol. 195, No. 3, 01.06.2003, p. 402-410.

Research output: Contribution to journalArticle

Costanzo, Antonio ; Moretti, Francesca ; Burgio, Vito Lelio ; Bravi, Cristina ; Guido, Francesco ; Levrero, Massimo ; Puri, Pier Lorenzo. / Endothelial activation by angiotensin II through NFκB and p38 pathways : Involvement of NFκB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin. In: Journal of Cellular Physiology. 2003 ; Vol. 195, No. 3. pp. 402-410.
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