title: Endothelial activation by angiotensin II through NFkappaB and p38 pathways: Involvement of NFkappaB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin.
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 (NFkappaB) activation is implicated in formation and progression of atherosclerotic plaque. Here we show that AII induces NFkappaB-dependent transcription in primary endothelial cell lines, leading to the upregulation of ICAM-1 and VCAM-1 expression. NFkappaB activation by AII is mediated by the NFkappaB-inducing kinase (NIK), a common mediator of NFkappaB activation by inflammatory cytokines, such as TNF-alpha. However, NFkappaB stimulation by AII differs from that of TNF-alpha since a TNF-receptor associated factor 2 (TRAF-2) dominant negative mutant does not prevent AII-mediated NFkappaB activation. In analogy with TNF-alpha-dependent activation of NFkappaB, 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 NFkappaB-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 NFkappaB. 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 NFkappaB target V-CAM, without affecting degradation of IkappaBalpha. These results support a pro-inflammatory effect of the vasoactive peptide AII in endothelial cells, through at least two pathways-NFkappaB and p38-both of which are sensitive to asp and antioxidants.
authors.affiliation: Laboratory of Gene Expression, Fondazione Andrea Cesalpino, Universita' degli Studi di Roma La Sapienza, Viale del Policlinico 155, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Costanzo
authors.forename: Francesca
authors.initials: F
authors.lastname: Moretti
authors.forename: Vito Lelio
authors.initials: VL
authors.lastname: Burgio
authors.forename: Cristina
authors.initials: C
authors.lastname: Bravi
authors.forename: Francesco
authors.initials: F
authors.lastname: Guido
authors.forename: Massimo
authors.initials: M
authors.lastname: Levrero
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000804:Angiotensin II; D001241:Aspirin; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D017382:Reactive Oxygen Species; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase