(Circulation. 2000;101:1234.)
© 2000 American Heart Association, Inc.
Brief Rapid Communications |
Vascular Effects Following Homozygous Disruption of p47phox
An Essential Component of NADPH Oxidase
From the Laboratory of Molecular Biology (E.H., T.F.) and the Laboratory of Animal Medicine and Surgery (J.D., R.F.H.), National Heart, Lung, and Blood Institute, and the Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (B.H.S., S.M.H.), National Institutes of Health, Bethesda, Md; The Jackson Laboratory, Bar Harbor, Maine (B.P.); and the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich (P.J.P, F.E.R).
Correspondence to Toren Finkel, MD, PhD, National Institutes of Health, Bldg 10-6N/240, 10 Center Drive, Bethesda, MD 20892. E-mail finkelt{at}nih.gov
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Evidence suggests that the vessel wall contains an oxidase similar, if not identical, to phagocytic NADPH oxidase. We tested the contribution of this specific oxidase to the progression of atherosclerosis and the regulation of blood pressure.
Methods and Results—An examination of aortic rings from wild-type mice and mice with homozygous targeted disruptions in p47phox revealed that p47phox knockout mice had a reduction in vascular superoxide production. However, analyses of apoE -/- p47phox+/+ and apoE -/- p47phox -/- strains of mice demonstrated no significant differences in atherosclerotic lesion sizes. Similarly, analyses of wild-type and p47phox knockout mice revealed no differences in either basal blood pressure or the rise in blood pressure seen after the pharmacological inhibition of nitric oxide synthase.
Conclusions—NADPH oxidase contributes to basal vascular superoxide production. However, the absence of a functional oxidase does not significantly affect the progression of atherosclerosis in the standard mouse apoE -/- model, nor does it significantly influence basal blood pressure.
Key Words: apolipoproteins • atherosclerosis • blood pressure
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The phagocytic NADPH oxidase generates superoxide through the assembly of a multi-subunit protein complex.1 Included in this complex are the 2 membrane-bound proteins gp91phox and p22phox, the recruited cytosolic oxidase proteins p47phox and p67phox, and the small GTPase rac2. Although initially the NADPH oxidase was thought to exist solely in phagocytes, recent evidence suggests that this oxidase may also function in nonphagocytic cells. Biochemically, NADH/NADPH activity has been detected in the intact vessel wall2 3 4 5 and in a variety of cultured vascular cells.6 7 In addition, the inhibition of p22phox lowers reactive oxygen species in smooth muscle cells,8 whereas the expression of constitutively active rac proteins in nonphagocytic cells augments the levels of reactive oxygen species.9 Similarly, all NADPH oxidase components have been detected by immunohistochemical staining of the vessel wall,7 10 11 and immunodepletion of p67phox from a vessel wall lysate reduces NADPH oxidase activity.7
Evidence also suggests a role for augmented NADPH oxidase activity in vascular disease. Consistent with this, the expression of certain components of the NADPH oxidase seems to be stimulated by angiotensin II and inflammatory cytokines.12 13 In addition, recent studies have also demonstrated that levels of p22phox are increased in human atherosclerotic plaque11 and in animal models of hypertension.14 In an effort to further address the precise role of NADPH oxidase, we analyzed the vascular effects of mice containing a targeted disruption of p47phox, an essential component of the phagocytic NADPH oxidase.15
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Mouse Genotyping and Physiological Analysis
C57BL/6J apoE -/- mice were obtained from Jackson Laboratories (Bar Harbor, Maine). For studies in atherogenesis, p47phox -/- mice were first backcrossed 10 generations with C57BL/6J mice. Three backcrosses of C57BL/6J mice containing either a targeted deletion in apoE or p47phox allowed for the isolation of certain F3 mice (apoE -/- p47phox+/+ or apoE -/- p47phox -/-) that were subsequently analyzed for atherosclerotic lesion size. Genotyping of animals was done with the apoE gene-specific primers 5'-GCCTAGCCGA-GGGAGAGCCG-3' and 5'-TGTGACTTGGGAGCTCTGCAGC-3' or the p47phox-specific primers 5'-ACATCACAGGCCCCAT-CATCCTCC-3' and 5'-CAACGTCGAGCACAGCTGCGCAAG-3'. Mice were fed a standard chow diet of 18% protein and 4% fat and maintained in a pathogen-free environment, but they were not given prophylactic antibiotics.
Atherosclerotic lesion size was determined at 16 weeks of age in male mice. After formalin fixation, the heart and ascending aorta were embedded and analyzed as previously described.16 Briefly, for each of the 17 mice in each group, 10-µm sections through the aortic sinus were obtained. Mean lesion size was determined by a blinded observer using a computer analysis of Oil red-O stained areas obtained from averaging 5 sections per animal.
Cholesterol levels were obtained from blood obtained from the retro-orbital plexus and analyzed by a commercial enzymatic test according to the manufacturer’s recommendations (Boehringer Mannheim Diagnostics). Blood pressure was determined in conscious animals by inserting a pressure-transducing cannula (Micro-Med TXD-310) into the left carotid artery. Animals used for blood pressure analysis were either p47phox -/- male mice (C57/BL6x129) or their wild-type male littermates. To inhibit nitric oxide synthase activity, 10 mg/kg of NG-nitro-L-arginine methyl ester (L-NAME) was injected into the peritoneal cavity; blood pressure was then assessed over the next 60 minutes.17
Levels of vascular superoxide were determined using lucigenin (25 µmol/L) chemiluminescence.8 To inhibit cellular superoxide dismutase (SOD) activity, rings were pretreated with 10 mmol/L diethyldithiocarbamate, as previously described.7 Statistical comparisons between groups were made with a 2-tailed Student’s t test; P<0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Levels of superoxide were assayed from aortic rings derived from p47phox knockout mice or their wild-type littermates. Basal superoxide levels were low, and no significant differences were observed between the wild-type and p47phox-deficient mice (Figure 1
). Because measured levels of superoxide
represent the balance between production and
degradation, we thought it possible that differences in superoxide
production might be more readily apparent in the absence of
cellular SOD activity. Thus, we pretreated rings with
diethyldithiocarbamate to selectively inhibit SOD activity, as
previously described.7 Under these conditions (Figure 1), significant differences were observed in superoxide levels,
with p47phox -/- mice having an 
50%
decrease in superoxide levels.
|
We next sought to understand whether animals containing a targeted
disruption of p47phox had altered in vivo
vascular pathophysiology. Two lines of mice were analyzed: one
contained a targeted disruption of apoE, and the other line contained
both an apoE and p47phox disruption. Both the
apoE- and p47phox-disrupted mice strains had been
previously backcrossed for 10 generations into a C57BL/6J background to
assure that these strains were otherwise genetically identical. The
apoE -/- p47phox+/+ and apoE -/-
p47phox -/- mice had equivalent serum
cholesterol levels (data not shown). In addition,
morphometric assessment of aortic lesion size revealed no differences
between the 2 groups (Figure 2A).
|
Given the known role of superoxide in regulating the bioactivity of
nitric oxide and, potentially, blood pressure, we next determined
whether we could detect differences in blood pressure between
p47phox-deficient mice and their wild-type
counterparts. As shown in Figure 2B
, basal blood pressure was
indistinguishable between the 2 strains of mice. Similarly, treatment
with L-NAME produced a similar increase in blood pressure in both
wild-type and p47phox knockout mice.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Our results demonstrate that the disruption of p47phox lowers vascular superoxide production. These results are, therefore, similar to those recently described in vascular preparations obtained from gp91phox-deficient mice.18 However, our data also suggest that the absence of a functional phagocytic NADPH oxidase does not significantly affect the progression of atherosclerosis in the apoE -/- mouse model, nor does it alter basal blood pressure.
This study may, therefore, seem to be in potential conflict with
previous studies indicating that superoxide levels rise in early
atherosclerosis and in models of
hypertension.5 19 20 21 22 One possible explanation for this
discrepancy is that the vessel wall may contain >1 NADPH oxidase
system. It is important to remember that almost all studies that have
demonstrated an increase in superoxide production attributable
to vascular NADPH oxidase activity have relied on biochemical assays or
pharmacological inhibitors. These approaches cannot define
the molecular components of the oxidase under study. Indeed, the
existence of >1 NADPH oxidase is strongly supported by the recent
isolation of mox1, a nonphagocytic homologue of
gp91phox that seems to generate superoxide
without requiring p47phox.23 In
addition, although our results (Figure 1) suggest that an
oxidase requiring p47phox contributes to vascular
superoxide production, this contribution was only evident after
inhibiting SOD activity. As such, under basal
physiological conditions, levels of superoxide were
unchanged and, therefore, it is perhaps not as surprising that no
effect on blood pressure or atherogenesis was evident. Similarly, the
observation that superoxide levels were only reduced by 50% in
p47phox knockout animals strongly suggests the
existence of additional vascular oxidases. Potential sources include
enzymes such as xanthine oxidases, lipoxygenases, and
novel NADPH oxidases that do not require p47phox
for activity. The use of knockout animals represents a
particularly promising approach to elucidate the relative contribution
of these multiple superoxide-generating enzymes in vascular
pathophysiology.
Received November 2, 1999; revision received December 29, 1999; accepted January 24, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. DeLeo FR, Quinn MT. Assembly of the phagocyte NADPH oxidase: molecular interaction of oxidase proteins. J Leukoc Biol. 1996;60:677–691.[Abstract]
2. Mohazzabh KM, Wolin MS. Properties of a superoxide anion-generating microsomal NADH oxidoreductase, a potential pulmonary-artery P-O2 sensor. Am J Physiol. 1994;11:L823–L831.
3. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–1923.[Medline] [Order article via Infotrieve]
4. Pagano PJ, Ito Y, Tornheim K, Gallop PM, Tauber AI, Cohen RA. An NADPH oxidase superoxide-generating system in the rabbit aorta. Am J Physiol.. 1995;37:H2274–H2280.
5. Griendling KK, UshioFakai M. NADPH/NADPH oxidase and vascular function. Trends Cardiovasc Med. 1997;7:301–307.
6.
Griendling KK, Minieri CA, Ollerenshaw JD, Alexander
RW. Angiotensin-II stimulates NADH and NADPH oxidase
activity in cultured vascular smooth-muscle cells. Circ Res. 1994;74:1141–1148.
7.
Pagano PJ, Clark JK, Cifuentes-Pagano ME, Clark SM,
Callis GM, Quinn MT. Localization of constitutively active,
phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement
by angiotensin II. Proc Natl Acad Sci U S A.. 1997;94:14483–14488.
8.
UshioFukai M, Zafari AM, Fukui T, Ishizaka N,
Griendling KK. P22(phox) is a critical component of the
superoxide-generating NADH/NADPH oxidase system and regulates
angiotensin II-induced hypertrophy in vascular
smooth muscle cells. J Biol Chem. 1996;271:23317–23321.
9. Sundaresan M, Yu ZX, Ferrans VJ, Sulciner DJ, Gutkind JS, Irani K, Godlschmidt-Clermont PJ, Finkel T. Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. Biochem J. 1996;318:379–382.
10.
Patterson C, Ruef J, Madamanchi NR, Barry-Lane P, Hu
ZY, Horaist C, Ballinger CA, Grasier AR, Bode C, Runge MS. Stimulation
of a vascular smooth muscle cell NAD(P)H oxidase by thrombin: evidence
that p47(phox) may participate in forming this oxidase in vitro and in
vivo. J Biol Chem. 1999;274:19814–19822.
11.
Azumi H, Inoue N, Takeshita S, Rikitake Y, Kawashima S,
Hayashi Y, Itoh H, Yokoyama M. Expression of NADH/NADPH oxidase
p22phox in human coronary arteries.
Circulation. 1999;100:1494–1498.
12. DeKeulenaer GW, Alexander RW, Ushio-Fukai M, Ishizaka N, Griendling KK. Tumor necrosis factor alpha activities a p22(phox)-based NADH oxidase in vascular smooth muscle. Biochem J. 1998;329:653–657.
13.
Pagano PJ, Chanock SJ, Siwik DA, Colucci WS, Clark JK.
Angiotensin II induces p67(phox) mRNA expression and NADPH
oxidase superoxide generation in rabbit aortic adventitial fibroblasts.
Hypertension. 1998;32:331–337.
14.
Fukui T, Ishizaka N, Rajagopalan S, Lauren JB, Capers
Q, Taylor WR, Harrison DG, deLeon H, Wilcox JN, Griendling KK. p22phox
mRNA expression and NADPH oxidase activity are increased in aortas from
hypertensive rats. Circ Res. 1997;80:45–51.
15.
Jackson SH, Gallin JI, Holland SM. The P47(phox) mouse
knock-out model of chronic granulomatous-disease. J Exp Med. 1995;182:751–758.
16. Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis. 1987;68:231–240.[Medline] [Order article via Infotrieve]
17.
Kurihara N, Alfie ME, Sigmon DH, Rhaleb NE, Shesely EG,
Carretero OA. Role of nNOS in blood pressure regulation in eNOS null
mutant mice. Hypertension. 1998;32:856–861.
18.
Archer SL, Reeve HL, Michelakis E, Puttagunta L, Waite
R, Nelson DP, Dinauer MC, Weir EK. O-2 sensing is preserved in mice
lacking the gp91 phox subunit of NADPH oxidase. Proc Natl Acad
Sci U S A.. 1999;96:7944–7949.
19. Harrison DG, Ohara Y. Physiological consequences of increased vascular oxidant stresses in hypercholesterolemia and atherosclerosis: implications for impaired vasomotion. Am J Cardiol. 1995;75:B75–B81.
20.
Miller FJ, Gutterman DD, Rios CD, Heistad DD, Davidson
BL. Superoxide production in vascular smooth muscle contributes
to oxidative stress and impaired relaxation in
atherosclerosis. Circ Res. 1998;82:1298–1305.
21.
Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen
JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm
M, Meinertz T, Munzel T. Increased NADH-oxidase-mediated superoxide
production in the early stages of
atherosclerosis: evidence for involvement of the
renin-angiotensin system. Circulation. 1999;99:2027–2033.
22.
Kerr S, Brosnan MJ, McIntyre M, Reid JL, Dominiczak AF,
Hamilton CA. Superoxide anion production is increased in a
model of genetic hypertension: role of the endothelium.
Hypertension. 1999;33:1353–1358.
23. Suh YA, Arnold RS, Lassegue B, Shi J, Xu XX, Sorescu D, Chung AB, Griendling KK, Lambeth JD. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999;401:79–82.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  D. Harb, K. Bujold, M. Febbraio, M. G. Sirois, H. Ong, and S. Marleau The role of the scavenger receptor CD36 in regulating mononuclear phagocyte trafficking to atherosclerotic lesions and vascular inflammation Cardiovasc Res, July 1, 2009; 83(1): 42 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. S. Bae, J. H. Lee, S. H. Choi, S. Kim, F. Almazan, J. L. Witztum, and Y. I. Miller Macrophages Generate Reactive Oxygen Species in Response to Minimally Oxidized Low-Density Lipoprotein: Toll-Like Receptor 4- and Spleen Tyrosine Kinase-Dependent Activation of NADPH Oxidase 2 Circ. Res., January 30, 2009; 104(2): 210 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Jun, V. Savransky, A. Nanayakkara, S. Bevans, J. Li, P. L. Smith, and V. Y. Polotsky Intermittent hypoxia has organ-specific effects on oxidative stress Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1274 - R1281. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Torzewski, V. Ochsenhirt, A. L. Kleschyov, M. Oelze, A. Daiber, H. Li, H. Rossmann, S. Tsimikas, K. Reifenberg, F. Cheng, et al. Deficiency of Glutathione Peroxidase-1 Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 850 - 857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Patwari and R. T. Lee Thioredoxins, Mitochondria, and Hypertension Am. J. Pathol., March 1, 2007; 170(3): 805 - 808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Grote, M. Ortmann, G. Salguero, C. Doerries, U. Landmesser, M. Luchtefeld, R. P. Brandes, W. Gwinner, T. Tschernig, E.-G. Brabant, et al. Critical role for p47phox in renin-angiotensin system activation and blood pressure regulation Cardiovasc Res, August 1, 2006; 71(3): 596 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Sethy-Coraci, L. W. Crock, and S. C. Silverstein PAF-receptor antagonists, lovastatin, and the PTK inhibitor genistein inhibit H2O2 secretion by macrophages cultured on oxidized-LDL matrices J. Leukoc. Biol., November 1, 2005; 78(5): 1166 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Doherty, P. K. Shah, M. Arditi, L. L. Stoll, G. M. Denning, and N. L. Weintraub Lipopolysaccharide, Toll-Like Receptors, and the Immune Contribution to Atherosclerosis Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): e38 - e39. [Full Text] [PDF]
|
|
|
|
 |
|
 R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Andresen, F. M. Faraci, and D. D. Heistad Vasomotor responses in MnSOD-deficient mice Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1141 - H1148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Chen, J. F. Keaney Jr., E. Schulz, B. Levison, L. Shan, M. Sakuma, X. Zhang, C. Shi, S. L. Hazen, and D. I. Simon Decreased neointimal formation in Nox2-deficient mice reveals a direct role for NADPH oxidase in the response to arterial injury PNAS, August 31, 2004; 101(35): 13014 - 13019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Li, S. Wheatcroft, L. M. Fan, M. T. Kearney, and A. M. Shah Opposing Roles of p47phox in Basal Versus Angiotensin II-Stimulated Alterations in Vascular O2- Production, Vascular Tone, and Mitogen-Activated Protein Kinase Activation Circulation, March 16, 2004; 109(10): 1307 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Cathcart Regulation of Superoxide Anion Production by NADPH Oxidase in Monocytes/Macrophages: Contributions to Atherosclerosis Arterioscler Thromb Vasc Biol, January 1, 2004; 24(1): 23 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kitiyakara, T. Chabrashvili, Y. Chen, J. Blau, A. Karber, S. Aslam, W. J. Welch, and C. S. Wilcox Salt Intake, Oxidative Stress, and Renal Expression of NADPH Oxidase and Superoxide Dismutase J. Am. Soc. Nephrol., November 1, 2003; 14(11): 2775 - 2782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Griendling and G. A. FitzGerald Oxidative Stress and Cardiovascular Injury: Part II: Animal and Human Studies Circulation, October 28, 2003; 108(17): 2034 - 2040. [Full Text] [PDF]
|
|
|
|
|
|
B. Lassegue and R. E. Clempus Vascular NAD(P)H oxidases: specific features, expression, and regulation Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2003; 285(2): R277 - R297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Brandes A Radical Adventure: The Quest for Specific Functions and Inhibitors of Vascular NAPDH Oxidases Circ. Res., April 4, 2003; 92(6): 583 - 585. [Full Text] [PDF]
|
|
|
|
|
|
F. E. Rey and P. J. Pagano The Reactive Adventitia: Fibroblast Oxidase in Vascular Function Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1962 - 1971. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion, M. J. Ryan, G. L. Baumbach, C. D. Sigmund, and F. M. Faraci Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen Am J Physiol Heart Circ Physiol, October 1, 2002; 283(4): H1569 - H1576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Van Heerebeek, C Meischl, W Stooker, C J L M Meijer, H W M Niessen, and D Roos NADPH oxidase(s): new source(s) of reactive oxygen species in the vascular system? J. Clin. Pathol., August 1, 2002; 55(8): 561 - 568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-p. Gao, T. J. Standiford, A. Rahman, M. Newstead, S. M. Holland, M. C. Dinauer, Q.-h. Liu, and A. B. Malik Role of NADPH Oxidase in the Mechanism of Lung Neutrophil Sequestration and Microvessel Injury Induced by Gram-Negative Sepsis: Studies in p47phox-/- and gp91phox-/- Mice J. Immunol., April 15, 2002; 168(8): 3974 - 3982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Lassegue and K. K. Griendling Out Phoxing the Endothelium: What's Left Without p47? Circ. Res., February 8, 2002; 90(2): 123 - 124. [Full Text] [PDF]
|
|
|
|
|
|
K. A. Gauss, P. L. Mascolo, D. W. Siemsen, L. K. Nelson, P. L. Bunger, P. J. Pagano, and M. T. Quinn Cloning and sequencing of rabbit leukocyte NADPH oxidase genes reveals a unique p67phox homolog J. Leukoc. Biol., February 1, 2002; 71(2): 319 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Zalba, G. S. Jose, M. U. Moreno, M. A. Fortuno, A. Fortuno, F. J. Beaumont, and J. Diez Oxidative Stress in Arterial Hypertension: Role of NAD(P)H Oxidase Hypertension, December 1, 2001; 38(6): 1395 - 1399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion, C. A. Hathaway, and F. M. Faraci Superoxide levels and function of cerebral blood vessels after inhibition of CuZn-SOD Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1697 - H1703. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Esworthy, R. Aranda, M. G. Martin, J. H. Doroshow, S. W. Binder, and F.-F. Chu Mice with combined disruption of Gpx1 and Gpx2 genes have colitis Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G848 - G855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Nilsson Absence of EC-SOD Does Not Promote Atherogenesis in Mice: Have We Lost Yet Another Player? Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1387 - 1388. [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Sentman, T. Brannstrom, S. Westerlund, M. O. Laukkanen, S. Yla-Herttuala, S. Basu, and S. L. Marklund Extracellular Superoxide Dismutase Deficiency and Atherosclerosis in Mice Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1477 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Husemann, A. Obstfeld, M. Febbraio, T. Kodama, and S. C. Silverstein CD11b/CD18 Mediates Production of Reactive Oxygen Species by Mouse and Human Macrophages Adherent to Matrixes Containing Oxidized LDL Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1301 - 1305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Lavigne, H. L. Malech, S. M. Holland, and T. L. Leto Genetic Demonstration of p47phox-Dependent Superoxide Anion Production in Murine Vascular Smooth Muscle Cells Circulation, July 3, 2001; 104(1): 79 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Y. Stokes, E. C. Clanton, J. M. Russell, C. R. Ross, and D. N. Granger NAD(P)H Oxidase-Derived Superoxide Mediates Hypercholesterolemia-Induced Leukocyte-Endothelial Cell Adhesion Circ. Res., March 16, 2001; 88(5): 499 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Pagano NAD(P)H Oxidase: Marker of the Dedifferentiated Neointimal Smooth Muscle Cell? Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 175 - 177. [Full Text] [PDF]
|
|
|
|
|
|
N. E. J. West, T. J. Guzik, E. Black, and K. M. Channon Enhanced Superoxide Production in Experimental Venous Bypass Graft Intimal Hyperplasia : Role of NAD(P)H Oxidase Arterioscler Thromb Vasc Biol, February 1, 2001; 21(2): 189 - 194. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Pagano Vascular gp91phox : Beyond the Endothelium Circ. Res., July 7, 2000; 87(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
|
|
T. J. Guzik, N. E. J. West, E. Black, D. McDonald, C. Ratnatunga, R. Pillai, and K. M. Channon Vascular Superoxide Production by NAD(P)H Oxidase : Association With Endothelial Dysfunction and Clinical Risk Factors Circ. Res., May 12, 2000; 86 (9): e85 - e90. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Dinauer, J. A. Lekstrom-Himes, and D. C. Dale Inherited Neutrophil Disorders: Molecular Basis and New Therapies Hematology, January 1, 2000; 2000(1): 303 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Brar, T. P. Kennedy, A. B. Sturrock, T. P. Huecksteadt, M. T. Quinn, T. M. Murphy, P. Chitano, and J. R. Hoidal NADPH oxidase promotes NF-kappa B activation and proliferation in human airway smooth muscle Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L782 - L795. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Didion and F. M. Faraci Effects of NADH and NADPH on superoxide levels and cerebral vascular tone Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H688 - H695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Wang, S. Xu, D. G. Johns, Y. Du, M. T. Quinn, A. J. Cayatte, and R. A. Cohen Role of NADPH Oxidase in the Vascular Hypertrophic and Oxidative Stress Response to Angiotensin II in Mice Circ. Res., May 9, 2001; 88(9): 947 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. E. Rey, M. E. Cifuentes, A. Kiarash, M. T. Quinn, and P. J. Pagano Novel Competitive Inhibitor of NAD(P)H Oxidase Assembly Attenuates Vascular O2- and Systolic Blood Pressure in Mice Circ. Res., August 31, 2001; 89(5): 408 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sorescu, D. Weiss, B. Lassegue, R. E. Clempus, K. Szocs, G. P. Sorescu, L. Valppu, M. T. Quinn, J. D. Lambeth, J. D. Vega, et al. Superoxide Production and Expression of Nox Family Proteins in Human Atherosclerosis Circulation, March 26, 2002; 105(12): 1429 - 1435. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||