doi: 10.1161/hq0102.102189
© 2002 American Heart Association, Inc.
Vascular Biology |
Upregulation of Nox-Based NAD(P)H Oxidases in Restenosis After Carotid Injury
From the Department of Medicine (K.S., B.L., D.S., L.L.H., L.V., K.K.G.), Division of Cardiology, the Winship Cancer Institute (T.L.C., J.N.W.), Division of Hematology/Oncology, and the Department of Biochemistry (J.D.L.), Emory University, Atlanta, Ga, and the Department of Veterinary Molecular Biology (M.T.Q.), Montana State University, Bozeman.
Correspondence to Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr, Atlanta, GA 30322. E-mail kgriend{at}emory.edu
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Abstract |
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Restenosis, a frequent complication of coronary angioplasty, is associated with increased superoxide (O2·-) production. Although the molecular identity of the responsible oxidase is unclear, an NAD(P)H oxidase appears to be involved. In smooth muscle, p22phox and 2 homologues of gp91phox, nox1 and nox4, are expressed, whereas fibroblasts contain gp91phox. To begin investigating the possibility that these oxidase components might contribute to the increased O2·- that accompanies neointimal formation, we measured their expression after balloon injury of the rat carotid artery. The increase in O2·- production 3 to 15 days after surgery was not due to inflammatory cell infiltration but appeared to be derived from medial and neointimal smooth muscle cells and adventitial fibroblasts. Nox1 and p22phox mRNAs were increased 2.7- and 3.6-fold, respectively, at day 3 after injury and remained elevated for 15 days. gp91Phox was increased 7 to 15 days after injury, and nox4 expression was increased 2-fold, but only at day 15 after surgery. These results confirm and extend our previous in vitro data and suggest that in the vasculature, the nox-based NAD(P)H oxidases serve different functions. This dynamic regulation of oxidase components may be critical to smooth muscle phenotypic modulation in restenosis and atherosclerosis.
Key Words: neointimal formation • superoxide • NAD(P)H oxidase • balloon injury • nox
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Introduction |
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Restenosis is a frequent complication of percutaneous transluminal coronary angioplasty. This pathophysiological process is characterized by arterial wall remodeling and intimal hyperplasia, resulting in luminal narrowing at the site of balloon dilation. Immediately after endothelial denudation, extensive death of medial smooth muscle cells (SMCs) occurs, which is then followed by significant proliferation of the remaining SMCs.1 These cells, together with activated adventitial cells (myofibroblasts), migrate through the internal elastic lamina to form the neointimal layer. The mechanisms responsible for the cellular events resulting in restenosis are incompletely understood.
See cover and page 4
In balloon-dilated arteries, superoxide (O2·-) production is increased not only as an early response of the vessel wall to injury2,3 but also 14 days after injury.4 Reactive oxygen species (ROS) are important mediators of SMC proliferation and migration,5 processes that lead to restenosis. Indeed, it has been shown that antioxidant treatment with probucol, L-cysteine, or butylated dihydroxytoluene reduces neointimal formation.6–8 Proliferating myocytes and fibroblasts produce ROS in the vessel wall,4,9 and a contribution by infiltrating macrophages has also been reported.10
The enzymatic source of O2·- production after balloon injury is unclear. Two groups have suggested that an NAD(P)H oxidase intrinsic to the vessel wall contributes to the increased O2·- production observed after injury; this suggestion was based on the ability of the flavoprotein inhibitor diphenylene iodonium to attenuate the elevated ROS levels ex vivo.9,11 However, there is little information about the molecular identity of the responsible oxidase. In SMCs, O2·- is produced mainly by an NAD(P)H oxidase,11,12 which shares some similarity to the phagocytic NADPH oxidase. Three of the 5 subunits of the neutrophil enzyme (p22phox, p47phox, and rac1) are present in SMCs. However, gp91phox, the subunit that is responsible for electron transfer and harbors the flavin-binding site, pyrimidine nucleotide–binding site, and heme-binding histidines, is expressed at barely detectable levels. We recently found that 2 gp91phox homologues, nox1 and nox4, are expressed at much higher levels than is gp91phox in SMCs and that nox1 is responsible for increased O2·- production, serum-induced mitogenesis, and activation of redox-sensitive signaling in vitro.13,14 This led us to hypothesize that a nox-based oxidase in smooth muscle may be upregulated in hyperproliferative vascular processes such as restenosis after balloon injury. We found that increased O2·- production in injured arteries was correlated with a global upregulation of p22phox, an upregulation of nox1 in SMCs, and an increase in gp91phox in cells of adventitial origin. In contrast, SMC nox4 was increased only at 15 days after injury. These observations suggest that the novel vascular NAD(P)H oxidases may contribute to the redox-sensitive process of neointimal formation after injury.
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Methods |
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Animal Model: Rat Carotid Balloon Injury
Sprague-Dawley rats (375 to 400 g) subjected to left common carotid artery injury by means of a 2F arterial embolectomy balloon catheter introduced into the external branch were purchased from Zivic-Miller Labortories (Zelienople, Pa). Carotid arteries were harvested 3, 7, 10, and 15 days after surgery, and loose adventitial tissue was removed from all samples. For RNA isolation, the tissue was snap-frozen in liquid nitrogen; for dihydroethidium (DHE) staining, in situ hybridization, and immunohistochemistry, samples were embedded in OCT (Tissue-Tek).
mRNA Assay by Real-Time Quantitative Polymerase Chain Reaction
Total RNA was purified from carotid arteries using RNeasy kit (Qiagen) and reverse-transcribed using Superscript (GIBCO). Quantification of p22phox, gp91phox, nox1, nox4, and 18S rRNA was performed by amplification of cDNA using LightCycler (Roche) real-time thermocycler. Copy numbers were calculated from standard curves generated from genuine rat nox1, nox4, gp91phox, p22phox, and 18S templates. Full details are given in the online supplement (which can be accessed at http://atvb.ahajournals.org).
Superoxide Detection
Frozen, enzymatically intact, 30-µm-thick sections of sham-operated and injured carotid arteries were incubated at the same time with DHE (10 µmol/L) in PBS for 30 minutes at 37°C in a humidified chamber protected from light. DHE is oxidized on reaction with O2·- to ethidium bromide, which binds to DNA in the nucleus and fluoresces red.15 For ethidium bromide detection, a 543-nm He-Ne laser combined with a 560-nm long-pass filter was used; for detecting the autofluorescence of the elastic laminae, a 488-nm argon laser combined with a 500- to 550-nm band-pass filter was used.
In Situ Hybridization
Nox1 and nox4 templates were transcribed with T7 RNA polymerase in the presence of [35S]UTP to generate 1212-bp nox1 and 952-bp nox4 antisense and 1315-bp nox1 and 1014-bp nox4 sense riboprobes. In situ hybridization was performed on OCT-embedded sections of injured and sham-operated rat carotid arteries, as previously described.16 After development, sections were counterstained with hematoxylin and eosin to aid in cell identification. Slides were photographed under polarized light epiluminescence microscopy (Leitz) so that silver grains appear white.
Immunofluorescence
Immunofluorescence was assessed using 7-µm OCT-embedded tissue sections fixed in acetone. Sections were incubated with primary antibodies (rabbit polyclonal p22phox antibody [1:100 dilution] and rabbit polyclonal nox4 antibody [1:100 dilution]; see online supplement for details of antibody preparation), mouse monoclonal anti–smooth muscle actin antibody (1:400 dilution), mouse monoclonal anti-gp91phox antibody (1:50 dilution), and macrophage-specific mouse anti-rat ED1 (1:400 dilution) in 1.0% BSA in PBS for 1 hour at room temperature. The sections were washed and incubated with secondary rhodamine red-X–labeled antibodies (1:50 dilution for goat anti-rabbit and 1:400 dilution for goat anti-mouse secondary antibody) for 30 minutes at room temperature. Some sections were counterstained with Hoechst for nuclear localization. Serial sections treated with secondary antibodies alone did not show specific staining. Carotid arteries from 2 or 3 animals for each time point and 3 sections per artery were evaluated. Samples were examined with a Zeiss LSM510 confocal microscope or with a Zeiss Axioskop microscope equipped with a computer-based imaging system.
Statistical Analysis
All data are expressed as mean±SEM. Statistical significance was assessed by ANOVA on untransformed data, followed by comparison of group averages by contrast analysis, using SuperANOVA statistical program (Abacus Concepts). A value of P<0.05 was considered to be statistically significant.
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Results |
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Superoxide Production in Injured Carotid Arteries
Previous data using lucigenin have suggested that balloon injury leads to an increase in O2·- production.17 However, this technique does not provide information concerning the location of O2·- production in situ. For this purpose, we used staining with DHE, which is specific for O2·-.15 A low-intensity fluorescence was observed throughout sham-operated vessels (Figure 1a through 1d), which confirms that all layers of the vessel wall normally produce low amounts of O2·-.15 As expected, coincubation with 300 U/mL liposomal superoxide dismutase nearly abolished the signal (not shown), proving the specificity for O2·-. Three days after the balloon injury of carotid arteries, O2·- production was increased in the adventitia and in the innermost medial layer but not in the remainder of the media (Figure 1e). Superoxide levels were clearly increased throughout the vessel wall 7 days after injury (Figure 1f), and greater increases were seen at days 10 and 15 (Figure 1g and 1h, respectively), when the staining was particularly strong in neointimal cells. This observation is consistent with in vitro studies suggesting that proliferating cells produce more O2·- than do cells of a quiescent phenotype.18
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Identification of O2·--Producing Cells
The potential role of inflammatory cells in neointimal formation after balloon injury in normocholesterolemic animals is controversial.19 Because activated macrophages are known to produce large amounts of O2·-, we investigated the extent of macrophage infiltration after injury and compared it with the pattern of O2·- generation observed by DHE staining of injured arteries. Histological sections were incubated with mouse anti-rat ED1 antibody, which recognizes the lysosomal membranes of myeloid cells (stains tissue macrophages and stains granulocytes weakly). As with the sections shown in Figure 1, loose adventitial connective tissue was removed before embedding. We did not detect a signal in the media or neointima in either sham-operated or injured specimens at any time point (days 3 and 15, shown in online Figure Ib through Ie; please see http://atvb.ahajournals.org). In contrast, the pattern of staining for smooth muscle 
-actin (detects SMCs and myofibroblasts) was similar to that obtained with DHE (Figure 2a through 2h). Although the staining was less intense in the intima, most cells were positive. These data suggest that in this model of injury, inflammatory cells are not responsible for O2·- production but that O2·- is localized to regions of the vessel wall containing SMC -actin–positive cells.
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Expression of NAD(P)H Oxidase Components After Balloon Injury
Recent data indicate that NAD(P)H oxidases are a major source of O2·- in the vessel wall.20 In SMCs, nox1 and p22phox are functionally important for NAD(P)H-driven O2·- production, and nox4 is highly expressed.14 To determine whether these molecules are upregulated after injury, the abundance of nox1, nox4, and p22phox mRNA was measured by real-time quantitative polymerase chain reaction. As an internal standard for normalization, the 18S rRNA transcript was used. On average, 25 copies of nox1 mRNA per 108 copies of 18S were detected in uninjured arteries. Nox1 levels were significantly increased in injured arteries throughout the time course. The highest upregulation was observed 3 days after surgery, when nox1 mRNA was 2.7-fold higher in injured compared with sham-operated arteries (Figure 3a). Similar to the pattern of nox1 mRNA expression, p22phox message was significantly increased in injured arteries over the entire time course, with the largest increase observed at 3 days after injury (3.6-fold, Figure 3b). In contrast, we did not detect differences in expression of nox4 between the 2 groups at 3, 7, or 10 days after injury. By day 15, however, the expression of nox4 in injured arteries was upregulated 2-fold (Figure 3c). This suggests that nox1, possibly in association with p22phox, is the component that correlates best with increased O2·- production during the development of the neointima. Nox4-derived O2·- production may contribute to later phases of neointimal thickening.
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To assess a possible contribution of the adventitial NADPH oxidase to O2·- production, we also examined gp91phox mRNA expression. We found a significant increase in gp91phox mRNA at 7 days (sham-operated arteries, 3174±1441copies per 108 18S; injured arteries, 10225±725 copies per 108 18S; n=3 and 5, respectively) and 15 days (sham-operated arteries, 2952±457 copies per 108 18S; injured arteries, 45955±10882 copies per 108 18S; n=5 and 4, respectively) after injury.
Localization of NAD(P)H Oxidase Subunits
To identify the cell types expressing NAD(P)H oxidase components, we chose 2 different approaches, in situ hybridization and immunohistochemistry. We have previously reported vascular in situ hybridization of p22phox.21 In the present study, we examined p22phox protein expression in injured arteries by using fluorescent immunohistochemistry. In sham-operated animals, p22phox protein was detected only in the adventitial layer (Figure 4), and the pattern of p22phox protein expression did not change up to 3 days after injury. By 7 days, p22phox protein was clearly present in the media and in the proliferating neointima as well, and by 10 to 15 days after injury, p22phox protein was most abundantly expressed in the neointima. Nox4 mRNA was readily detected in medial and neointimal cells at 15 days after injury (Figure 5A). Nox4 protein was found in the media of sham-operated arteries and in the neointima beginning at 10 days, and it was increased throughout the vessel wall at 15 days (Figure 5B). Of interest, nox4 expression preceded the reappearance of the differentiation marker calponin (Figure 5B, bottom row), suggesting that nox4 may be correlated with differentiation rather than growth (see below). The expression of gp91phox was limited to the adventitia in sham-operated animals, but 10 to 15 days after injury, staining became evident in isolated locations in the media, and some neointimal cells began to express gp91phox (Figure 6). We were unable to localize nox1 mRNA and protein in these tissues because of low copy numbers and the unavailability of a rodent anti-nox1 antibody. Overall, these data are consistent with our mRNA measurements.
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Discussion |
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In the present study, we provide the first evidence for upregulation of the novel gp91phox homologues nox1 and nox4 in vascular pathophysiology. Although other investigators have reported that restenosis is accompanied by an increase in O2·- production from flavin-containing enzymes,9,11 there have been no reports addressing the regulation of the specific enzyme systems that produce ROS. We also show that balloon injury of the carotid artery results in an increase in O2·- production throughout the vessel wall for at least 15 days after the initial injury. This increase in O2·- is not due to infiltration of inflammatory cells but appears to be derived from SMCs in the media and neointima as well as from adventitial cells. Expression of the NAD(P)H oxidase components nox1, gp91phox, and p22phox is increased concomitantly with the elevation in O2·- levels. A late increase in nox4 expression also occurs. These data provide support for a dynamic regulation of NAD(P)H oxidase components during hyperproliferative vascular disorders and raise the possibility that nox-based enzymes are involved in the restenotic process.
Studies with antioxidants provide evidence of a causal role for ROS in neointimal formation. These agents reduce neointimal proliferation and promote vessel remodeling in several animal models.4,6,7 Antioxidants potentially exert their effects by interfering with several processes leading to neointimal formation. Immediately after injury, extensive apoptosis of medial SMCs occurs; this is an event that is attenuated by the antioxidant N-acetylcysteine.3 Approximately 24 hours later, medial SMC and adventitial myofibroblast proliferation begins. Dedifferentiated cells then migrate across the internal elastic lamina and replicate in response to growth factors, with maximal proliferation by 7 to 10 days.1,22 In vitro, SMC proliferation is clearly dependent on redox-sensitive activation of specific signaling pathways,5,13,20 and migration also requires ROS production.5 By 14 days, SMC proliferation has diminished, and redifferentiation has begun (Weiser-Evans et al22 and Christen et al23 and Figure 5B); this event has also recently been shown to be redox sensitive.24 Thus, O2·- may contribute to restenosis by multiple mechanisms.
Several previous studies have shown increased O2·- production in balloon-injured carotid arteries using chemiluminescent techniques and nitro blue tetrazolium. Elevated levels of ROS have been observed immediately after injury2,3 and between 1 and 14 days after injury.4,6,9 In contrast, Azevedo et al25 found no increase in O2·- production at 14 and 28 days in balloon-injured rabbit iliac arteries. Using DHE, we were able to semiquantitatively detect O2·- production throughout the 15-day time course (Figure 1) and to localize its cellular sources in the vessel wall. By 7 days after injury, we observed that O2·- was elevated in all regions of the wall, especially the neointima and adventitia. Only one other study attempted to localize O2·- production within the vessel wall. Shi et al9 reported an increase in O2·- in the adventitia, which we also detected, even though the majority of the adventitia was removed from our preparations. These observations suggest that the oxidases responsible for the increased O2·- production after balloon injury reside in SMCs and myofibroblasts.
Studies using pharmacological inhibitors targeting specific ROS-generating pathways indicate that vascular O2·- production is largely due to membrane-associated flavin-containing enzymes that use NADH or NADPH as substrates,20 similar to the NADPH oxidase of inflammatory cells. However, involvement of these latter cells in neointimal formation is minimal (Pollman et al3 and Figures I [online] and 2), indicating that they are not primarily responsible for the increase in ROS. The vascular NAD(P)H oxidases actually represent a family of enzymes homologous to the phagocytic oxidase with different subunit compositions. In neutrophils, the full electron transport function of the respiratory burst NAD(P)H oxidase resides in gp91phox, which combines with p22phox to form cytochrome b558. This subunit is also responsible for O2·- generation in fibroblasts.26 However, in SMCs, gp91phox is expressed at very low levels,14 and experiments with aortic tissue from gp91phox-deficient mice indicate that this subunit of the phagocytic oxidase is not responsible for O2·- generation in smooth muscle.11 In SMCs, the gp91phox homologues nox1 and nox4 are expressed to a much higher degree, and nox1 has been shown to mediate agonist-induced O2·- production.14 The function of nox4 in SMCs is currently unknown but may be related to the inhibition of cell growth on the basis of observations in fibroblasts.27
Over the initial phase of neointimal formation, nox1, gp91phox, and p22phox messages are elevated (Figure 3) and appear to be correlated with O2·- production. Although p22phox protein and increased O2·- generation are detectable in the adventitia by day 3, an increase in these parameters is evident across the vessel wall by day 7 (Figures 1 and 4). This suggests that several cell types contribute to the pathological response. Previous work has shown that the population of cells in the neointima is heterogeneous and may arise from cells of medial and adventitial origin.28 We found that neointimal cells express multiple nox homologues (Figures 5 and 6), supporting the concept that SMCs (which express only nox1 and nox4) and adventitial cells (which express gp91phox) contribute to neointimal formation. These nox homologues are likely to mediate different pathophysiological events, because gp91phox-based oxidases produce O2·- intracellularly and extracellularly,29 whereas nox1- and nox4-based oxidases generate O2·- mainly intracellularly (Figure 1 and Griendling et al12 and Lassègue et al14). For example, whereas O2·- can inactivate NO both intracellularly and extracellularly, intracellular O2·- and its metabolite H2O2 have been shown to activate specific molecular targets leading to growth and migration.20 Thus, in restenosis, nox1 and p22phox may be involved in inducible O2·- generation in proliferating cells, in confirmation of in vitro studies,14 whereas gp91phox-based oxidases may contribute to growth by blocking the growth-inhibitory functions of NO.
The increase in O2·- generation across the vessel wall, together with the more limited distribution of NAD(P)H oxidase subunits (Figures 1 and 4 through 6), suggests that other oxidases may contribute to O2·- production as well. This may be particularly important for basal O2·- generation, which is not correlated with p22phox protein levels (Figures 1a through 1d and 4). Several other oxidases have been implicated, including cytochrome P-450 and NO synthase,30,31 and our data raise the possibility that nox4 might contribute as well. Nox4 is highly expressed in sham-operated arteries (Figure 3) in a pattern similar to that of O2·- (compare Figure 1a through 1d with Figure 5). Unlike nox1, gp91phox, and p22phox, its expression is unchanged until 15 days after injury (Figures 3b and 5f). At this time point, SMC proliferation has diminished, as detected by bromodeoxyuridine staining32; reendothelialization and redifferentiation are beginning (Weiser-Evans et al22 and Christen et al23 and Figure 5); and matrix deposition is increasing. Thus, it is possible that nox4, by virtue of a specific intracellular activity and distribution, contributes to the later events of restenosis, perhaps including the redox-sensitive process of differentiation.24 Taken together, these data suggest that nox1 and nox4 have distinct regulatory roles.
The need for more than one NAD(P)H oxidase catalytic subunit is somewhat paradoxical. It is likely that the activation mechanisms and capacity of nox1 and nox4 differ. Normally, nox4 mRNA expression is 
150 times higher than nox1 mRNA expression, but growth factors increase the expression and output of nox1, leading to an increase in O2·- production.14 In contrast, antisense to nox4 decreases basal, but not agonist-induced, O2·- generation (A. DiKalova, B. Lassègue, K. Griendling, unpublished data, 2001). This suggests that nox1 may produce large amounts of O2·- when required (important for growth), whereas nox4 may mediate steady production of low amounts of O2·- that are important in the metabolic and differentiation functions of the cell. Confirmation of the exact role of gp91phox homologues in regulating the mechanisms responsible for neointimal formation will require further experiments with nox1 and nox4 knockout mice when they become available.
In summary, O2·- production was increased in injured carotid arteries. Induction of nox1, gp91phox, and p22phox mRNAs preceded nox4 upregulation, indicating that these components of vascular oxidases are likely to play different roles in redox-sensitive arterial remodeling. Upregulation of gp91phox homologues and p22phox may contribute to increased vascular oxidative stress in hyperproliferative vascular disorders, such as restenosis after balloon angioplasty.
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Acknowledgments |
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This work was supported by National Institutes of Health grants HL-38206, HL-58863, HL-58000, HL-57908, and HL-66575 and an American Heart Association Fellowship to K.S. We thank Dr Imajoh-Ohmi for her kind gift of the p22phox antibody.
Received October 8, 2001; accepted November 5, 2001.
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R. Jones, M. B. Baker, M. Weber, D. G. Harrison, G. Bao, and C. D. Searles Molecular beacons can assess changes in expression and 3'-polyadenylation of human eNOS mRNA Am J Physiol Cell Physiol, March 1, 2009; 296(3): C498 - C504. [Abstract] [Full Text] [PDF]
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S. Basuroy, S. Bhattacharya, C. W. Leffler, and H. Parfenova Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-{alpha} in cerebral vascular endothelial cells Am J Physiol Cell Physiol, March 1, 2009; 296(3): C422 - C432. [Abstract] [Full Text] [PDF]
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D. Meng, D.-D. Lv, and J. Fang Insulin-like growth factor-I induces reactive oxygen species production and cell migration through Nox4 and Rac1 in vascular smooth muscle cells Cardiovasc Res, November 1, 2008; 80(2): 299 - 308. [Abstract] [Full Text] [PDF]
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J.-M. Li, M. Mogi, J. Iwanami, L.-J. Min, K. Tsukuda, A. Sakata, T. Fujita, M. Iwai, and M. Horiuchi Temporary Pretreatment With the Angiotensin II Type 1 Receptor Blocker, Valsartan, Prevents Ischemic Brain Damage Through an Increase in Capillary Density Stroke, July 1, 2008; 39(7): 2029 - 2036. [Abstract] [Full Text] [PDF]
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M. J. Haurani, M. E. Cifuentes, A. D. Shepard, and P. J. Pagano Nox4 Oxidase Overexpression Specifically Decreases Endogenous Nox4 mRNA and Inhibits Angiotensin II-Induced Adventitial Myofibroblast Migration Hypertension, July 1, 2008; 52(1): 143 - 149. [Abstract] [Full Text] [PDF]
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A. Whaley-Connell, J. Habibi, R. Nistala, S. A. Cooper, P. R. Karuparthi, M. R. Hayden, N. Rehmer, V. G. DeMarco, B. T. Andresen, Y. Wei, et al. Attenuation of NADPH Oxidase Activation and Glomerular Filtration Barrier Remodeling With Statin Treatment Hypertension, February 1, 2008; 51(2): 474 - 480. [Abstract] [Full Text] [PDF]
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K. Tsukuda, M. Mogi, J.-M. Li, J. Iwanami, L.-J. Min, A. Sakata, T. Fujita, M. Iwai, and M. Horiuchi Diabetes-Associated Cognitive Impairment Is Improved by a Calcium Channel Blocker, Nifedipine Hypertension, February 1, 2008; 51(2): 528 - 533. [Abstract] [Full Text] [PDF]
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L.-J. Min, M. Mogi, J. Iwanami, J.-M. Li, A. Sakata, T. Fujita, K. Tsukuda, M. Iwai, and M. Horiuchi Cross-talk between aldosterone and angiotensin II in vascular smooth muscle cell senescence Cardiovasc Res, December 1, 2007; 76(3): 506 - 516. [Abstract] [Full Text] [PDF]
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S. J. An, R. Boyd, M. Zhu, A. Chapman, D. R. Pimentel, and H. D. Wang NADPH oxidase mediates angiotensin II-induced endothelin-1 expression in vascular adventitial fibroblasts Cardiovasc Res, September 1, 2007; 75(4): 702 - 709. [Abstract] [Full Text] [PDF]
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E. C. Chan, S. R. Datla, R. Dilley, H. Hickey, G. R. Drummond, and G. J. Dusting Adventitial application of the NADPH oxidase inhibitor apocynin in vivo reduces neointima formation and endothelial dysfunction in rabbits Cardiovasc Res, September 1, 2007; 75(4): 710 - 718. [Abstract] [Full Text] [PDF]
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A. Sturrock, T. P. Huecksteadt, K. Norman, K. Sanders, T. M. Murphy, P. Chitano, K. Wilson, J. R. Hoidal, and T. P. Kennedy Nox4 mediates TGF-beta1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells Am J Physiol Lung Cell Mol Physiol, June 1, 2007; 292(6): L1543 - L1555. [Abstract] [Full Text] [PDF]
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H. Abdala-Valencia, J. Earwood, S. Bansal, M. Jansen, G. Babcock, B. Garvy, M. Wills-Karp, and J. M. Cook-Mills Nonhematopoietic NADPH oxidase regulation of lung eosinophilia and airway hyperresponsiveness in experimentally induced asthma Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1111 - L1125. [Abstract] [Full Text] [PDF]
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G. Zalba, A. Fortuno, J. Orbe, G. San Jose, M. U. Moreno, M. Belzunce, J. A. Rodriguez, O. Beloqui, J. A. Paramo, and J. Diez Phagocytic NADPH Oxidase-Dependent Superoxide Production Stimulates Matrix Metalloproteinase-9: Implications for Human Atherosclerosis Arterioscler Thromb Vasc Biol, March 1, 2007; 27(3): 587 - 593. [Abstract] [Full Text] [PDF]
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R. E. Clempus, D. Sorescu, A. E. Dikalova, L. Pounkova, P. Jo, G. P. Sorescu, B. Lassegue, and K. K. Griendling Nox4 Is Required for Maintenance of the Differentiated Vascular Smooth Muscle Cell Phenotype Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 42 - 48. [Abstract] [Full Text] [PDF]
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D. C. Fernandes, J. Wosniak Jr., L. A. Pescatore, M. A. Bertoline, M. Liberman, F. R. M. Laurindo, and C. X. C. Santos Analysis of DHE-derived oxidation products by HPLC in the assessment of superoxide production and NADPH oxidase activity in vascular systems Am J Physiol Cell Physiol, January 1, 2007; 292(1): C413 - C422. [Abstract] [Full Text] [PDF]
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K. Kappert, J. Sparwel, A. Sandin, A. Seiler, U. Siebolts, O. Leppanen, S. Rosenkranz, and A. Ostman Antioxidants Relieve Phosphatase Inhibition and Reduce PDGF Signaling in Cultured VSMCs and in Restenosis Arterioscler Thromb Vasc Biol, December 1, 2006; 26(12): 2644 - 2651. [Abstract] [Full Text] [PDF]
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A. Oshita, M. Iwai, R. Chen, A. Ide, M. Okumura, S. Fukunaga, T. Yoshii, M. Mogi, J. Higaki, and M. Horiuchi Attenuation of Inflammatory Vascular Remodeling by Angiotensin II Type 1 Receptor-Associated Protein Hypertension, October 1, 2006; 48(4): 671 - 676. [Abstract] [Full Text] [PDF]
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J. Suzuki, M. Iwai, M. Mogi, A. Oshita, T. Yoshii, J. Higaki, and M. Horiuchi Eplerenone With Valsartan Effectively Reduces Atherosclerotic Lesion by Attenuation of Oxidative Stress and Inflammation Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 917 - 921. [Abstract] [Full Text] [PDF]
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M. Okumura, M. Iwai, A. Ide, M. Mogi, M. Ito, and M. Horiuchi Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT2 Receptor Expression Hypertension, September 1, 2005; 46(3): 577 - 583. [Abstract] [Full Text] [PDF]
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M. Weber, C. H. Hagedorn, D. G. Harrison, and C. D. Searles Laminar Shear Stress and 3' Polyadenylation of eNOS mRNA Circ. Res., June 10, 2005; 96(11): 1161 - 1168. [Abstract] [Full Text] [PDF]
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T. Tojo, M. Ushio-Fukai, M. Yamaoka-Tojo, S. Ikeda, N. Patrushev, and R. W. Alexander Role of gp91phox (Nox2)-Containing NAD(P)H Oxidase in Angiogenesis in Response to Hindlimb Ischemia Circulation, May 10, 2005; 111(18): 2347 - 2355. [Abstract] [Full Text] [PDF]
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D. Zhuang, A.-C. Ceacareanu, B. Ceacareanu, and A. Hassid Essential role of protein kinase G and decreased cytoplasmic Ca2+ levels in NO-induced inhibition of rat aortic smooth muscle cell motility Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1859 - H1866. [Abstract] [Full Text] [PDF]
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T. Djordjevic, R. S. BelAiba, S. Bonello, J. Pfeilschifter, J. Hess, and A. Gorlach Human Urotensin II Is a Novel Activator of NADPH Oxidase in Human Pulmonary Artery Smooth Muscle Cells Arterioscler Thromb Vasc Biol, March 1, 2005; 25(3): 519 - 525. [Abstract] [Full Text] [PDF]
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H. M. Dourron, G. M. Jacobson, J. L. Park, J. Liu, D. J. Reddy, M. L. Scheel, and P. J. Pagano Perivascular gene transfer of NADPH oxidase inhibitor suppresses angioplasty-induced neointimal proliferation of rat carotid artery Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H946 - H953. [Abstract] [Full Text] [PDF]
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N. R. Madamanchi, A. Vendrov, and M. S. Runge Oxidative Stress and Vascular Disease Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 29 - 38. [Abstract] [Full Text] [PDF]
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R. P. Brandes and J. Kreuzer Vascular NADPH oxidases: molecular mechanisms of activation Cardiovasc Res, January 1, 2005; 65(1): 16 - 27. [Abstract] [Full Text] [PDF]
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H. Zhang, D. Chalothorn, L. F. Jackson, D. C. Lee, and J. E. Faber Transactivation of Epidermal Growth Factor Receptor Mediates Catecholamine-Induced Growth of Vascular Smooth Muscle Circ. Res., November 12, 2004; 95(10): 989 - 997. [Abstract] [Full Text] [PDF]
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Z. Li, M. Iwai, L. Wu, H.-W. Liu, R. Chen, T. Jinno, J. Suzuki, M. Tsuda, X.-Y. Gao, M. Okumura, et al. Fluvastatin Enhances the Inhibitory Effects of a Selective AT1 Receptor Blocker, Valsartan, on Atherosclerosis Hypertension, November 1, 2004; 44(5): 758 - 763. [Abstract] [Full Text] [PDF]
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S. Wassmann, K. Wassmann, and G. Nickenig Modulation of Oxidant and Antioxidant Enzyme Expression and Function in Vascular Cells Hypertension, October 1, 2004; 44(4): 381 - 386. [Abstract] [Full Text] [PDF]
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M. Yokoyama and N. Inoue How Vascular NAD(P)H Oxidase Activity and Nox Isoform Expression are Regulated Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1540 - 1541. [Full Text] [PDF]
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M. Iwai, H.-W. Liu, R. Chen, A. Ide, S. Okamoto, R. Hata, M. Sakanaka, T. Shiuchi, and M. Horiuchi Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation Circulation, August 17, 2004; 110(7): 843 - 848. [Abstract] [Full Text] [PDF]
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E. L. Schiffrin and R. M. Touyz From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H435 - H446. [Full Text] [PDF]
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C. Zhang, J. Yang, and L. K. Jennings Attenuation of neointima formation through the inhibition of DNA repair enzyme PARP-1 in balloon-injured rat carotid artery Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H659 - H666. [Abstract] [Full Text] [PDF]
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P. C. Schulze, J. Yoshioka, T. Takahashi, Z. He, G. L. King, and R. T. Lee Hyperglycemia Promotes Oxidative Stress through Inhibition of Thioredoxin Function by Thioredoxin-interacting Protein J. Biol. Chem., July 16, 2004; 279(29): 30369 - 30374. [Abstract] [Full Text] [PDF]
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C. Taille, J. El-Benna, S. Lanone, M.-C. Dang, E. Ogier-Denis, M. Aubier, and J. Boczkowski Induction of Heme Oxygenase-1 Inhibits NAD(P)H Oxidase Activity by Down-regulating Cytochrome b558 Expression via the Reduction of Heme Availability J. Biol. Chem., July 2, 2004; 279(27): 28681 - 28688. [Abstract] [Full Text] [PDF]
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D. Zhuang, A.-C. Ceacareanu, Y. Lin, B. Ceacareanu, M. Dixit, K. E. Chapman, C. M. Waters, G. N. Rao, and A. Hassid Nitric oxide attenuates insulin- or IGF-I-stimulated aortic smooth muscle cell motility by decreasing H2O2 levels: essential role of cGMP Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2103 - H2112. [Abstract] [Full Text] [PDF]
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D. S. Weber, Y. Taniyama, P. Rocic, P. N. Seshiah, M. A. Dechert, W. T. Gerthoffer, and K. K. Griendling Phosphoinositide-Dependent Kinase 1 and p21-Activated Protein Kinase Mediate Reactive Oxygen Species-Dependent Regulation of Platelet-Derived Growth Factor-Induced Smooth Muscle Cell Migration Circ. Res., May 14, 2004; 94(9): 1219 - 1226. [Abstract] [Full Text] [PDF]
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 K K Griendling Novel NAD(P)H oxidases in the cardiovascular system Heart, May 1, 2004; 90(5): 491 - 493. [Full Text] [PDF]
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J. D. van Buul and P. L. Hordijk Signaling in Leukocyte Transendothelial Migration Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 824 - 833. [Abstract] [Full Text]
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T. Shiuchi, M. Iwai, H.-S. Li, L. Wu, L.-J. Min, J.-M. Li, M. Okumura, T.-X. Cui, and M. Horiuchi Angiotensin II Type-1 Receptor Blocker Valsartan Enhances Insulin Sensitivity in Skeletal Muscles of Diabetic Mice Hypertension, May 1, 2004; 43(5): 1003 - 1010. [Abstract] [Full Text] [PDF]
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L. L. Hilenski, R. E. Clempus, M. T. Quinn, J. D. Lambeth, and K. K. Griendling Distinct Subcellular Localizations of Nox1 and Nox4 in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 677 - 683. [Abstract] [Full Text] [PDF]
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G. A. Kaysen and J. P. Eiserich The Role of Oxidative Stress-Altered Lipoprotein Structure and Function and Microinflammation on Cardiovascular Risk in Patients with Minor Renal Dysfunction J. Am. Soc. Nephrol., March 1, 2004; 15(3): 538 - 548. [Abstract] [Full Text] [PDF]
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G. Cheng and J. D. Lambeth NOXO1, Regulation of Lipid Binding, Localization, and Activation of Nox1 by the Phox Homology (PX) Domain J. Biol. Chem., February 6, 2004; 279(6): 4737 - 4742. [Abstract] [Full Text] [PDF]
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T. Jinno, M. Iwai, Z. Li, J.-M. Li, H.-W. Liu, T.-X. Cui, H. Rakugi, T. Ogihara, and M. Horiuchi Calcium Channel Blocker Azelnidipine Enhances Vascular Protective Effects of AT1 Receptor Blocker Olmesartan Hypertension, February 1, 2004; 43(2): 263 - 269. [Abstract] [Full Text] [PDF]
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T. Ago, T. Kitazono, H. Ooboshi, T. Iyama, Y. H. Han, J. Takada, M. Wakisaka, S. Ibayashi, H. Utsumi, and M. Iida Nox4 as the Major Catalytic Component of an Endothelial NAD(P)H Oxidase Circulation, January 20, 2004; 109(2): 227 - 233. [Abstract] [Full Text] [PDF]
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T. Bleeke, H. Zhang, N. Madamanchi, C. Patterson, and J. E. Faber Catecholamine-Induced Vascular Wall Growth Is Dependent on Generation of Reactive Oxygen Species Circ. Res., January 9, 2004; 94(1): 37 - 45. [Abstract] [Full Text] [PDF]
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J. Hwang, M. H. Ing, A. Salazar, B. Lassegue, K. Griendling, M. Navab, A. Sevanian, and T. K. Hsiai Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression: Implication for Native LDL Oxidation Circ. Res., December 12, 2003; 93(12): 1225 - 1232. [Abstract] [Full Text] [PDF]
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R. P. Brandes Out of Balance: A Role of Impaired Superoxide Dismutase Activity for Vascular Constrictive Remodeling After Angioplasty Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2121 - 2122. [Full Text] [PDF]
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P. F. Leite, A. Danilovic, P. Moriel, K. Dantas, S. Marklund, A. P. V. Dantas, and F. R.M. Laurindo Sustained Decrease in Superoxide Dismutase Activity Underlies Constrictive Remodeling After Balloon Injury in Rabbits Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2197 - 2202. [Abstract] [Full Text] [PDF]
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Y. Taniyama and K. K. Griendling Reactive Oxygen Species in the Vasculature: Molecular and Cellular Mechanisms Hypertension, December 1, 2003; 42(6): 1075 - 1081. [Abstract] [Full Text] [PDF]
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J. Hwang, A. Saha, Y. C. Boo, G. P. Sorescu, J. S. McNally, S. M. Holland, S. Dikalov, D. P. Giddens, K. K. Griendling, D. G. Harrison, et al. Oscillatory Shear Stress Stimulates Endothelial Production of O2- from p47phox-dependent NAD(P)H Oxidases, Leading to Monocyte Adhesion J. Biol. Chem., November 21, 2003; 278(47): 47291 - 47298. [Abstract] [Full Text] [PDF]
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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]
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D. Gregg, F. M. Rauscher, and P. J. Goldschmidt-Clermont Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch Am J Physiol Cell Physiol, October 1, 2003; 285(4): C723 - C734. [Abstract] [Full Text] [PDF]
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 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]
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M. E. Cifuentes and P. J. Pagano c-Src and Smooth Muscle NAD(P)H Oxidase: Assembling a Path to Hypertrophy Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 919 - 921. [Full Text] [PDF]
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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]
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G. M. Jacobson, H. M. Dourron, J. Liu, O. A. Carretero, D. J. Reddy, T. Andrzejewski, and P. J. Pagano Novel NAD(P)H Oxidase Inhibitor Suppresses Angioplasty-Induced Superoxide and Neointimal Hyperplasia of Rat Carotid Artery Circ. Res., April 4, 2003; 92(6): 637 - 643. [Abstract] [Full Text] [PDF]
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Z. Ungvari, A. Csiszar, J. G. Edwards, P. M. Kaminski, M. S. Wolin, G. Kaley, and A. Koller Increased Superoxide Production in Coronary Arteries in Hyperhomocysteinemia: Role of Tumor Necrosis Factor-{alpha}, NAD(P)H Oxidase, and Inducible Nitric Oxide Synthase Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 418 - 424. [Abstract] [Full Text] [PDF]
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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]
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K. M. Channon Oxidative Stress and Coronary Plaque Stability Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1751 - 1752. [Full Text] [PDF]
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N. L. Weintraub Nox Response to Injury Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 4 - 5. [Full Text] [PDF]
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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]
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