Role of p47(phox) in vascular oxidative stress and hypertension caused by angiotensin II.
Hypertension caused by angiotensin II is dependent on vascular superoxide (O2*-) production. The nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase is a major source of vascular O2*- and is activated by angiotensin II in vitro. However, its role in angiotensin II-induced hypertension in vivo is less clear. In the present studies, we used mice deficient in p47(phox), a cytosolic subunit of the NADPH oxidase, to study the role of this enzyme system in vivo. In vivo, angiotensin II infusion (0.7 mg/kg per day for 7 days) increased systolic blood pressure from 105+/-2 to 151+/-6 mm Hg and increased vascular O2*- formation 2- to 3-fold in wild-type (WT) mice. In contrast, in p47(phox-/-) mice the hypertensive response to angiotensin II infusion (122+/-4 mm Hg; P<0.05) was markedly blunted, and there was no increase of vascular O2*- production. In situ staining for O2*- using dihydroethidium revealed a marked increase of O2*-production in both endothelial and vascular smooth muscle cells of angiotensin II-treated WT mice, but not in those of p47(phox-/-) mice. To directly examine the role of the NAD(P)H oxidase in endothelial production of O2*-, endothelial cells from WT and p47(phox-/-) mice were cultured. Western blotting confirmed the absence of p47(phox) in p47(phox-/-) mice. Angiotensin II increased O2*- production in endothelial cells from WT mice, but not in those from p47(phox-/-) mice, as determined by electron spin resonance spectroscopy. These results suggest a pivotal role of the NAD(P)H oxidase and its subunit p47(phox) in the vascular oxidant stress and the blood pressure response to angiotensin II in vivo.
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases; D018384:Oxidative Stress; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D010750:Phosphoproteins; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013481:Superoxides; D000804:Angiotensin II; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1
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