Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress.
The recruitment of monocytes via the endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) is a key step in the formation of the initial lesion in atherosclerosis. Because angiotensin (Ang) II may be involved in this process, we investigated its role on the signaling cascade leading to VCAM-1 expression in endothelial cells. Ang II stimulates mRNA and protein expression of VCAM-1 in these cells via the AT(1) receptor. This effect was enhanced by N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, and blocked by pyrrolidinedithiocarbamate, an antioxidant molecule. Ang II activated the redox-sensitive transcription factor nuclear factor-kappaB and stimulated the degradation of both inhibitor of kappaB (IkappaB)alpha and IkappaBbeta with different kinetics. The degradation of IkappaBs induced by Ang II was not modified by incubation with exogenous superoxide dismutase and catalase, suggesting that this effect was not mediated by the extracellular production of O(2)(-). In contrast, rotenone and antimycin, 2 inhibitors of the mitochondrial respiratory chain, inhibited the Ang II-induced IkappaB degradation, showing that generation of reactive oxygen species in the mitochondria is involved on Ang II action. BXT-51702, a glutathione peroxidase mimic, inhibited the effect of Ang II, and aminotriazole, an inhibitor of catalase, enhanced it, suggesting a role for H(2)O(2) in IkappaB degradation. This is confirmed by experiments showing that Ang II stimulates the intracellular production of H(2)O(2) in endothelial cells. These results demonstrate that Ang II induced an intracellular oxidative stress in endothelial cells, which stimulates IkappaB degradation and nuclear factor-kappaB activation. This activation enhances the expression of VCAM-1 and probably other genes involved in the early stages of atherosclerosis.
Pueyo
M E
ME
INSERM U460, Paris, France. pueyo@infobiogen.fr
Gonzalez
W
W
Nicoletti
A
A
Savoie
F
F
Arnal
J F
JF
Michel
J B
JB
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D020672:I-kappa B Proteins; D008928:Mitochondria / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D019010:Vascular Cell Adhesion Molecule-1; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; D000072000:NF-KappaB Inhibitor alpha; D006861:Hydrogen Peroxide