gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension.
BACKGROUND
Isoforms of the NADPH oxidase contribute to vascular superoxide anion (*O2-) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O2- to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction.


RESULTS
Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox-/-) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox-/- mice (158+/-2 versus 149+/-2 mm Hg; P<0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox-/- mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox-/- mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox-/- mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice.


CONCLUSIONS
These data indicate that the formation of O2- by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.
Jung
O
O
Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt am Main, Germany.
Schreiber
J G
JG
Geiger
H
H
Pedrazzini
T
T
Busse
R
R
Brandes
R P
RP
D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta; D001427:Bacterial Toxins / Q000494:pharmacology; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology; D045303:Cytochromes b / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006023:Glycoproteins / Q000494:pharmacology; D006978:Hypertension, Renovascular / Q000150:complications / Q000201:enzymology* / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009569:Nitric Oxide / Q000378:metabolism*; D009924:Organ Culture Techniques; D011092:Polyethylene Glycols / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000975:Antioxidants; D001427:Bacterial Toxins; C488583:Clostridium difficile lethal toxin B; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D007211:Indoles; D008562:Membrane Glycoproteins; D011799:Quinazolines; D020032:Tyrphostins; D014665:Vasodilator Agents; C473031:gp91ds-tat protein, chimeric; D013481:Superoxides; D000804:Angiotensin II; C101044:RTKI cpd; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D045303:Cytochromes b; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D000109:Acetylcholine; C064758:Ro 31-8220