Abstract-Oxygen-derived free radicals are involved in the vascular response to angiotensin II (Ang II), but the role of NADPH oxidase, its subunit proteins, and their vascular localization remain controversial. Our purpose was to address the role of NADPH oxidase in the blood pressure (BP) Although a role of NADPH oxidase in Ang II-induced hypertension has been widely reported, the vascular location and the role of various subunit proteins of the oxidase have been controversial. NADPH oxidase subunits, including gp91 phox , are expressed in endothelial cells in culture. [5][6][7] Our group has shown that the adventitia is also an important site of superoxide anion production in normal rat 8 and rabbit aorta, 9 and NADPH oxidase subunits, including gp91 phox , are found in native 8 and cultured 10 adventitial fibroblasts. The oxidase accounts for the majority of superoxide anion production in the adventitia, where it has been implicated in inactivating NO. 8,9,11 Furthermore, superoxide anion is increased by Ang II-induced hypertension, 1 particularly in the adventitia. 9,11 In addition, we proposed that the increased superoxide anion generated in the aortic adventitia of Ang II-induced hypertensive rats was responsible for spontaneous myogenic tone, which was in part due to the inactivation of the endogenous vasodilator NO. 12 NADPH oxidase has been studied most in leukocytes, where it is stimulated as part of the oxidative burst. Vascular NADPH oxidase differs in that it appears to be constitutively active, and its activity is stimulated by Ang II. 13 A fibroblast NADPH oxidase was reported to have a cytochromecontaining subunit that differed from the gp91 phox in the neutrophil NADPH oxidase. 14 In addition, it has been reported that superoxide anion production by the aorta of the gp91 phox mouse is the same as that of wild-type mice. 15 Although a constitutively active homolog of gp91 phox , MOX-1, has been cloned, 16 and which might explain this discrepancy, its role in intact blood vessels is not yet known.,The purpose of this study was to further address the role of superoxide anion derived from NADPH oxidase in the pressor, vascular hypertrophic, and oxidant responses during Ang II-dependent hypertension. We took advantage of mice that are genetically deficient in gp91 phox to determine the role of this specific subunit of the oxidase. These mice have been used previously to study the role of gp91 phox and NADPH oxidase as an oxygen sensor in vivo. 17 Our findings indicate Original
To determine if endogenous local levels of nitric oxide (NO) modulate atherogenesis, we studied the effect of inhibiting NO with A fO -nitro-L-arginine methyl ester (L-NAME) on early neointima formation in cholesterol-fed rabbits. Male rabbits were fed for 5 weeks with a 0.5% cholesterol diet alone or treated in addition during the last 4 weeks with L-NAME (12 mg/kg per day SC) via osmotic minipump. Endothelial cell function was assessed in isolated aortic rings by vascular reactivity and levels of cyclic GMP. In L-NAME-treated rabbits there was inhibition of endotheliumdependent relaxations to acetylcholine and the calcium ionophore A23187 as well as impaired cyclic GMP accumulation in response to acetylcholine. Neointima formation in the ascending thoracic aorta was assessed by determining media and intima cross-sectional areas with computerized image analysis. N itric oxide (NO), a potent physiological vasodilator that accounts for the biological activities of endothelium-derived relaxing factor, 1 is synthesized in endothelial cells from the terminal guanidino nitrogen of L-arginine by the constitutive calciumcalmodulin-NADPH-dependent enzyme NO synthase (NOS). 2 In humans and animals with hypercholesterolemia-induced atherosclerosis, endothelium-dependent vasodilation is impaired, 35 suggesting reduced NO synthesis or action. NO has antiproliferative actions on vascular cells, 6 -7 supporting the hypothesis that the endothelial cell dysfunction observed in hypercholesterolemia could contribute to the initiation and progression of the atherosclerotic neointima. When administered in the diet of cholesterol-fed rabbits, the NO precursor L-arginine limits development of aortic atherosclerosis and improves endothelial cell function. 8 - 9 We recently reported 10 a technique for the chronic administration to rabbits of the NOS inhibitor iV G -nitro-L-arginine methyl ester ( L -N A M E ) and demonstrated its persistent systemic effects on endothelial cells and Received November 22, 1993; revision accepted February 11, 1994.From the Robert Dawson Evans Department of Clinical Research, Vascular Biology Unit, Boston University School of Medicine, Boston, Mass.Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 6-11, 1993, and published in abstract form in Circulation. 1993;88(pt 2):I-366.Correspondence to Antonio J. Cayatte, MD, Vascular Biology Unit, E-401, Department of Medicine, Boston University School of Medicine, Boston, MA 02118.Compared with rabbits that consumed the cholesterol diet alone, L-NAME-treated rabbits had significant increases in lesion area (0.29+0.04 versus 0.15±0.03 mm 2 ) and in lesion/ media ratio (0.06±0.01 versus 0.03±0.01). Plasma levels of cholesterol and fluorescent lipid peroxide products were unchanged, suggesting no difference in cholesterol metabolism or oxidation. Because arterial blood pressure was not altered by L-NAME treatment, the increased atherogenesis could not be attributed to an increase in blood pressure. mi...
Abstract-The purpose of this study was to determine whether superoxide anion is produced endogenously in the rat aortic adventitia and whether sufficient superoxide anion is produced to interfere with the response of the rat aorta to nitric oxide. Relaxation was measured in rings of the rat thoracic aorta, which were oriented so that the adventitial or luminal surface could be preferentially exposed to nitric oxide or sodium nitroprusside. To accomplish this, the rings were mounted (1) with the adventitia facing outward, (2) with the adventitia facing inward after inverting, or (3) with the adventitia facing outward after inverting twice (to control for the inverting procedure). The relaxation to nitric oxide, but not to sodium nitroprusside, was less in rings with the adventitia facing outward compared with those in which it faced inward. In contrast, the response to nitric oxide via either surface was similar when extracellular superoxide anion was scavenged with superoxide dismutase. Incubation of rings with nitro blue tetrazolium (NBT) resulted in blue formazan staining of the adventitia, and lucigenin chemiluminescence was significantly greater when detected from the adventitial compared with the intimal aspect of the artery. The reduction of NBT in intact aortic rings was 30Ϯ2 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1 and was significantly decreased by superoxide dismutase to 19Ϯ2 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1 and by a synthetic superoxide dismutase mimic, Euk-8, to 11Ϯ2 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1. The NADPH oxidase inhibitor, diphenyleneiodonium, decreased NBT reduction to 9Ϯ1 pmol ⅐ min Ϫ1 ⅐ mg Ϫ1, whereas inhibitors of xanthine oxidase, mitochondrial oxidases, and nitric oxide synthase were ineffective. Immunohistochemical staining indicated the localization of NADPH oxidase proteins gp91 phox , p22 phox , p47 phox , and p67 phox almost exclusively in the adventitia of the rat aorta with no substantial staining in the media. These results indicate that NADPH oxidase located in the adventitia of rat thoracic aorta generates sufficient extracellular superoxide anion to constitute a barrier capable of inactivating nitric oxide. This study suggests that adventitial superoxide anion can play a role in the pathophysiology of the arterial wall. (Circ Res. 1998;82:810-818.)
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