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Hypertension. 2001;38:1395-1399
doi: 10.1161/hy1201.099611
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(Hypertension. 2001;38:1395.)
© 2001 American Heart Association, Inc.

Fourth International Seminar on Cardiovascular Biology and Medicine: Part II

Oxidative Stress in Arterial Hypertension

Role of NAD(P)H Oxidase

Guillermo Zalba; Gorka San José; María U. Moreno; María A. Fortuño; Ana Fortuño; Francisco J. Beaumont; Javier Díez

From the Division of Cardiovascular Pathophysiology, School of Medicine (G.Z., G.S.J., M.U.M., M.A.F., A.F., F.J.B., J.D.), and the Department of Cardiology and Cardiovascular Surgery, University Clinic (J.D.), University of Navarra, Pamplona, Spain.

Correspondence to Guillermo Zalba, PhD, División de Fisiopatología Vascular, Facultad de Medicina, C/Irunlarrea s/n, 31080 Pamplona, Spain. E-mail gzalba{at}unav.es

Abstract

Increased vascular reactive oxygen species production, especially superoxide anion, contributes significantly in the functional and structural alterations present in hypertension. An enhanced superoxide production causes a diminished NO bioavailability by an oxidative reaction that inactivates NO. Exaggerated superoxide levels and a low NO bioavailability lead to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that the enzyme NAD(P)H oxidase plays a major role as the most important source of superoxide anion in vascular cells. Several experimental observations have shown an enhanced superoxide generation as a result of the activation of vascular NAD(P)H oxidase in hypertension. Although this enzyme responds to stimuli such as vasoactive factors, growth factors, and cytokines, some recent data suggest the existence of a genetic background modulating the expression of its different components. New polymorphisms have been identified in the promoter of the p22phox gene, an essential subunit of NAD(P)H oxidase, influencing the activity of this enzyme. Genetic investigations of these polymorphisms will provide novel markers for determination of genetic susceptibility to oxidative stress in hypertension.


Key Words: angiotensin II • genetics • hypertension, arterial • stress • free radicals

Large amounts of reactive oxygen species (ROS), resulting from oxygen, are produced in vascular cells, including superoxide anion (·O2-) and hydrogen peroxide (H2O2), and act as important intracellular signals. Oxidative stress describes the injury caused to cells by the oxidizing of macromolecules resulting from increased formation of ROS and/or decreased antioxidant reserve. Recent works have reported that all types of vascular cells generate ROS. A growing number of reports have provided a critical role for oxidative stress in the pathogenesis of cardiovascular diseases, including hypertension.1

An enhanced production of ROS contributes to the dysregulation of physiological processes, which leads to structural and functional alterations in hypertension.2 Two characteristic alterations of the vascular wall in hypertension are endothelial dysfunction and vascular smooth muscle cell (VSMC) hypertrophy. An enhanced production of ROS causes a loss of NO bioavailability, which impairs endothelial function, causing (among others) a decreased endothelium-dependent vasodilation.3 Among these ROS, ·O2- is critically involved in the breakdown of NO.4 Thus, a diminished availability of NO can be the result of a decreased activity from the NO-production pathway or the result of an increase in the oxidative inactivation of NO by ·O2-. Recently, we have shown that endothelial dysfunction is associated with an excess of ·O2- generation rather than a diminished NO production in the aorta of adult spontaneously hypertensive rats (SHR).5 The presence of unpaired electrons causes ·O2- to be chemically unstable and highly reactive. The reaction of ·O2- with NO leads to the production of peroxynitrite,6 a potent oxidant believed to be responsible for tissue injury. Peroxynitrite induces the oxidation of proteins, DNA, and lipids in vascular cells.7 On the other hand, recent findings suggest that increased ROS may stimulate VSMC hypertrophy and hyperplasia.8 Li et al9 has shown that ·O2- induces the proliferation of VSMCs, and Zafari et al10 has proposed a role for ·O2- and H2O2 in angiotensin II-induced VSMC hypertrophy. ROS are also involved in several signal pathways and in the activation of redox-sensitive transcriptional factors, such as nuclear factor (NF)-kB.11 It has been shown recently that angiotensin II activates NF-{kappa}B in VSMCs.12 Furthermore, NF-{kappa}B has been implicated in the transcription of a number of vascular genes.13 Finally, NF-{kappa}B seems to play a pivotal role in angiotensin II-stimulated ROS generation and inflammatory mechanisms (see review14).

Vascular NAD(P)H Oxidase

Enzymatic sources of ROS in the vascular wall playing a functional role in hypertension are NAD(P)H oxidase, NO synthase, xanthine oxidase, and cyclooxygenase. Vascular NAD(P)H oxidase, which is to some extent similar to the previously reported neutrophil NADPH oxidase, is the most important source of ·O2- in vascular cells.15–18 The structure and function of this vascular oxidase has been recently reviewed.8 At present, response to extracellular NAD(P)H is one of the major unanswered questions concerning membrane orientation and function of this oxidase.19 Vascular NAD(P)H oxidase consists of a cytochrome b558, composed of p22phox and gp91phox subunits and 3 cytosolic components, p47phox, p67phox, and rac. The Table summarizes the expression of these components in vascular cells. Transfection of antisense p22phox demonstrated this subunit of the cytochrome to be essential for functionality of NAD(P)H oxidase.20 Disruption of gp91phox and p47phox subunits lowers vascular ·O2- production, without significant alterations in basal blood pressure.21,22 Thus, the existence of compensatory mechanisms regulating blood pressure in this knockout mouse cannot be discarded. Although the gp91phox subunit is absent in VSMCs, the presence of functional isoforms, Nox1 and Nox4, has been reported.23,24 Recently, it has been shown that Nox1 mediates angiotensin II-induced ·O2- formation and redox-sensitive signaling pathways in VSMCs.24 Vascular NAD(P)H oxidase is a constitutive enzyme, but it can be also regulated by humoral factors, such as angiotensin II, platelet-derived growth factor, thrombin, tumor growth factor-{alpha}, and glucocorticoids,18,25–28 and hemodynamic forces, including laminar and oscillatory shear stress.29


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  		Table 1. Expression of NAD(P)H Oxidase Components in Vascular Cells

NAD(P)H Oxidase in Experimental Hypertension
Angiotensin II-Induced Hypertension
Rajagopalan et al30 demonstrated that chronic infusion of angiotensin II in rats resulted in hypertension in correlation with an increased NAD(P)H oxidase-derived ·O2- generation. In the same study, these alterations were corrected by pretreatment of the rats with losartan. Fukui et al31 reported that increased activity of NAD(P)H oxidase in angiotensin II-induced hypertension activated NAD(P)H oxidase by upregulating the p22phox mRNA levels, a critical component of this oxidase.20 Infusion of recombinant heparin-binding superoxide dismutase (SOD) decreased both blood pressure and p22phox mRNA expression.31

Recent evidence also suggests the involvement of other subunits in angiotensin II-induced hypertension. Thus, in aortas from angiotensin II-infused mice, there is an increased NAD(P)H-driven ·O2- production concomitant with increased protein levels of p67phox and gp91phox subunits that is associated with the elevation of blood pressure.32 Furthermore, these angiotensin II-induced increases were normalized by simultaneous treatment with losartan.

DOCA-Salt and Renovascular Hypertension
Somers et al33 showed an enhanced vascular ·O2- production associated with impaired endothelium-dependent relaxation in deoxycorticosterone acetate (DOCA)-salt rats, a hypertension model characterized by a low plasma renin activity. Recently, Wu et al34 have reported that the enhanced ·O2- production present in the aorta of DOCA-salt hypertensive rats is associated with an increased NADH oxidase activity. It seems that this increased oxidase activity is independent of the rise in blood pressure. It has been suggested that an increased vascular angiotensin II release as a consequence of nephrectomy is the origin of the increased NADH oxidase activity in these rats.

Renovascular hypertension in the 2-kidney, 1-clip rat model depends on an increase in circulating angiotensin II levels.35 In this model, NO production is increased,36 and a potential role for ·O2- in enhanced NO breakdown has been suggested. Heitzer et al37 showed an increased aortic ·O2- generation in this hypertension model associated with an overactivity of NAD(P)H oxidase. Although the mechanism whereby angiotensin II activates NAD(P)H oxidase is still unclear, it might involve a protein kinase C-dependent process.

Genetic Hypertension
Several works have recently provided evidence confirming the pathophysiological function of ROS in the SHR. Suzuki et al38 showed an increased ·O2- generation in venules and arterioles in these hypertensive rats. Furthermore, Nakazono et al39 demonstrated that administration within the vessel wall of heparin-binding SOD normalized the blood pressure of SHR. Recently, we reported an enhanced NAD(P)H oxidase-driven ·O2- production associated with an upregulated p22phox mRNA expression in the aorta of adult SHR with endothelial dysfunction and vascular wall hypertrophy.40

In the same work, NAD(P)H oxidase-driven ·O2- production was not increased in young SHR, which discards a critical role of hypertension in the regulation of oxidase. In this regard, it has been reported that in norepinephrine-induced hypertension, neither ·O2- production nor NAD(P)H oxidase is increased.30 Interestingly, we found that both p22phox mRNA expression and NAD(P)H oxidase activity were normalized in adult SHR treated with the angiotensin II type 1 (AT1) receptor antagonist irbesartan.40 This suggests a critical role of angiotensin II in the upregulation of this oxidase in the adult SHR. This possibility is further supported by the fact that enhanced expression of both AT1 receptor and ACE have been reported in vessels of adult SHR.41 As a consequence of an overactivity of the renin-angiotensin system, changes in the degree of activation of vascular cells can regulate p22phox expression. In this regard, we observed that differences in the VSMC phenotype were correlated with changes in the p22phox gene promoter activity.42 Thus, p22phox gene promoter activity was increased in VSMCs isolated from adult SHR compared with those obtained from normotensive Wistar-Kyoto rats (WKY).

On the other hand, upregulation of the oxidase p22phox subunit in the SHR may be consequence of alterations in the sequence of the p22phox gene. In this way we identified 5 polymorphisms in the promoter region of the SHR p22phox gene (Figure 1). Interestingly, the polymorphic SHR promoter possessed functional significance, suggesting that these polymorphisms might be involved in overexpression of the p22phox gene in the vascular wall of the SHR.42 Taken together, these findings suggest that besides changes in degree of activation of VSMCs associated with the development of hypertension in SHR, the presence of several polymorphisms in the promoter region of the p22phox gene might contribute to the upregulation of p22phox in the vessel wall of SHR. Increased p22phox expression is attenuated by SOD in hypertensive animals, suggesting a role for ·O2- itself in the regulation of p22phox expression.31 Interestingly, we have described 2 putative consensus binding sites for NF-{kappa}B in the strong positive regulatory region of the rat p22phox promoter.42



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  		Figure 1. Influence of cellular phenotype and gene polymorphisms on p22phox subunit expression. A, Existence of polymorphisms between normotensive WKY and SHR p22phox promoter. ATG represents the translation initiation codon. B, Transfection experiments with the SHR polymorphic promoter (P) and the WKY control promoter (C) into VSMCs from WKY and SHR. Histograms express relative luciferase activity of the p22phox promoter. *P<0.05 vs WKY control promoter, by Student’s t test. (This figure is an adaptation.42)

In another model of genetic hypertension, Kerr et al43 showed a diminished NO bioavailability as a consequence of an enhanced vascular ·O2- production in 12- to 16-week-old stroke-prone SHR (SHR-SP) and suggested a critical role of the endothelium and endothelial NO synthase as sources of the ·O2- generation. Hamilton et al44 have recently described similar results in old (9- to 12-month) SHR-SP. Interestingly, in this last report, they showed that apocynin, a specific inhibitor of NAD(P)H oxidase subunit assembly, decreased the enhanced ·O2- production present in the aortic wall of both 3- to 4-month-old and 9- to 12-month-old SHR-SP. From these results, a contributing role of NAD(P)H oxidase in vascular ·O2- generation in this model of hypertension could be hypothesized.

NAD(P)H Oxidase in Human Essential Hypertension
Clinical studies have shown the occurrence of increased ROS production in humans with essential hypertension.45,46 In physiological conditions, ·O2- levels are modulated by endogenous scavenging systems, such as SOD. It seems that in essential hypertension, it should be an unbalance between an enhanced ·O2- generation and a decreased antioxidant activity. In fact, the levels of ROS scavengers, such as vitamin E, glutathione, and SOD, have been reported to be depressed in hypertensive patients.47 Furthermore, vitamin C recovers endothelial function by restoring the NO-mediated vasodilation of the endothelium in hypertensive patients.48

Berry et al49 have demonstrated that NAD(P)H oxidase is a source of basal ·O2- production in human internal mammary arteries and saphenous veins. The same authors have reported that angiotensin II increases ·O2- in human arteries. This effect is mediated by NAD(P)H oxidase and is completely inhibited by the AT1 receptor antagonist losartan. Higher basal ·O2- concentration in arteries, compared with that in veins, was maintained after endothelial denudation by rubbing, suggesting that VSMCs might be an important source of ·O2- generation in the human arterial wall. Up to now, no studies have been published dealing with vascular NAD(P)H oxidase activity in human hypertension.

Although the relationship between AT1 receptor and NAD(P)H oxidase activity is fascinating, several studies do not show a beneficial effect of ACE inhibitors and AT1 antagonists on endothelial function in patients with essential hypertension.50,51 On the other hand, results with these drugs are more convincing in patients with coronary artery disease.52 Thus, the possibility exists that NAD(P)H oxidase could play a role in patients with a greater cardiovascular risk.

Guzik et al53 have reported a functional effect of the C242T p22phox polymorphism in the p22phox gene on NAD(P)H oxidase-driven ·O2- production in the vascular wall of patients with atherosclerosis. Recently, Schachinger et al54 described an association of the C242T p22phox polymorphism with coronary endothelial vasodilator function. Gardemann et al55 showed that the association of the A640G polymorphism in the p22phox gene with the presence and extent of coronary artery disease was stronger in hypertensive than in normotensive subjects. Thus, the role of p22phox polymorphisms via NAD(P)H oxidase-mediated ·O2- production in the development of atherosclerosis in essential hypertension can be hypothesized.

Conclusion and Perspectives
Arterial hypertension is associated with an enhanced vascular production of ROS, namely, ·O2-. Overactivity of NAD(P)H oxidase may be critically involved in such an alteration (Figure 2). Thus, this enzyme may play a role in endothelial dysfunction and vascular hypertrophy present in hypertension (Figure 2). Besides hemodynamic factors, humoral factors such as angiotensin II may be responsible for altered NAD(P)H oxidase in hypertension (Figure 2), thus allowing for specific pharmacological interventions aimed to reduce oxidative stress in hypertension. The possibility also exists that p22phox gene promoter polymorphisms might regulate NAD(P)H oxidase-driven ·O2- production in hypertensive patients. Nevertheless, to confirm that these polymorphisms of the p22phox gene are novel markers for hypertensive oxidative stress, investigations in large populations are necessary.



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  		Figure 2. NAD(P)H oxidase activation and functional consequences in arterial hypertension. AII indicates angiotensin II; PDGF, platelet-derived growth factor; and TNF-{alpha}, tumor necrosis factor-{alpha}. Multiple humoral agonists and hemodynamic forces activate NAD(P)H oxidase. Genetic changes may be involved by modulating the expression of the components of NAD(P)H oxidase. An enhanced superoxide anion production driven by NAD(P)H oxidase activation is involved in endothelial dysfunction by decreasing NO bioavailability and is involved in media hypertrophy through the production of H2O2.

Received August 8, 2001; first decision August 15, 2001; accepted September 10, 2001.

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 Evid Based Complement Alternat MedHome page
V. Kumar, M. M. Khan, A. K. Khanna, R. Singh, S. Singh, R. Chander, F. Mahdi, A. A. Mahdi, J. K. Saxena, and R. K. Singh
Lipid Lowering Activity of Anthocephalus indicus Root in Hyperlipidemic Rats
Evid. Based Complement. Altern. Med., February 4, 2008; (2008) nen001v1.
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 Diabetes CareHome page
E. Grossman
Does Increased Oxidative Stress Cause Hypertension?
Diabetes Care, February 1, 2008; 31(Supplement_2): S185 - S189.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
H. Macarthur, T. C. Westfall, and G. H. Wilken
Oxidative stress attenuates NO-induced modulation of sympathetic neurotransmission in the mesenteric arterial bed of spontaneously hypertensive rats
Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H183 - H189.
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 HypertensionHome page
L. F. Lien, A. J. Brown, J. D. Ard, C. Loria, T. P. Erlinger, A. C. Feldstein, P.-H. Lin, C. M. Champagne, A. C. King, H. L. McGuire, et al.
Effects of PREMIER Lifestyle Modifications on Participants With and Without the Metabolic Syndrome
Hypertension, October 1, 2007; 50(4): 609 - 616.
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 HypertensionHome page
X. Cao, X. Dai, L. M. Parker, and D. L. Kreulen
Differential Regulation of NADPH Oxidase in Sympathetic and Sensory Ganglia in Deoxycorticosterone Acetate Salt Hypertension
Hypertension, October 1, 2007; 50(4): 663 - 671.
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 Eur Heart JHome page
L. Loffredo, A. Marcoccia, P. Pignatelli, P. Andreozzi, M.C. Borgia, R. Cangemi, F. Chiarotti, and F. Violi
Oxidative-stress-mediated arterial dysfunction in patients with peripheral arterial disease
Eur. Heart J., March 1, 2007; 28(5): 608 - 612.
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 Physiol. Rev.Home page
K. Bedard and K.-H. Krause
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Physiol Rev, January 1, 2007; 87(1): 245 - 313.
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 J. Am. Soc. Nephrol.Home page
S. V. Shah, R. Baliga, M. Rajapurkar, and V. A. Fonseca
Oxidants in Chronic Kidney Disease
J. Am. Soc. Nephrol., January 1, 2007; 18(1): 16 - 28.
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 Exp PhysiolHome page
J. W. Weiss, M. D. Y. Liu, and J. Huang
Sleep Apnoea & Hypertension: Physiological bases for a causal relation: Physiological basis for a causal relationship of obstructive sleep apnoea to hypertension
Exp Physiol, January 1, 2007; 92(1): 21 - 26.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
G. Zhang, F. Zhang, R. Muh, F. Yi, K. Chalupsky, H. Cai, and P.-L. Li
Autocrine/paracrine pattern of superoxide production through NAD(P)H oxidase in coronary arterial myocytes
Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H483 - H495.
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 DiabetesHome page
J. Park, S. S. Choe, A H. Choi, K. H. Kim, M. J. Yoon, T. Suganami, Y. Ogawa, and J. B. Kim
Increase in Glucose-6-Phosphate Dehydrogenase in Adipocytes Stimulates Oxidative Stress and Inflammatory Signals
Diabetes, November 1, 2006; 55(11): 2939 - 2949.
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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. Yzydorczyk, F. Gobeil Jr., G. Cambonie, I. Lahaie, N. L. O. Le, S. Samarani, A. Ahmad, J. C. Lavoie, L. L. Oligny, P. Pladys, et al.
Exaggerated vasomotor response to ANG II in rats with fetal programming of hypertension associated with exposure to a low-protein diet during gestation
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1060 - R1068.
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 Arterioscler. Thromb. Vasc. Bio.Home page
T. J. Guzik, J. Sadowski, B. Guzik, A. Jopek, B. Kapelak, P. Przybylowski, K. Wierzbicki, R. Korbut, D. G. Harrison, and K. M. Channon
Coronary Artery Superoxide Production and Nox Isoform Expression in Human Coronary Artery Disease
Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 333 - 339.
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 J. Pharmacol. Exp. Ther.Home page
F. Jimenez-Altayo, A. M. Briones, J. Giraldo, A. M. Planas, M. Salaices, and E. Vila
Increased Superoxide Anion Production by Interleukin-1{beta} Impairs Nitric Oxide-Mediated Relaxation in Resistance Arteries
J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 42 - 52.
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 DiabetesHome page
A. Fortuno, G. San Jose, M. U. Moreno, O. Beloqui, J. Diez, and G. Zalba
Phagocytic NADPH Oxidase Overactivity Underlies Oxidative Stress in Metabolic Syndrome
Diabetes, January 1, 2006; 55(1): 209 - 215.
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 HypertensionHome page
M. Akishita, K. Nagai, H. Xi, W. Yu, N. Sudoh, T. Watanabe, M. Ohara-Imaizumi, S. Nagamatsu, K. Kozaki, M. Horiuchi, et al.
Renin-Angiotensin System Modulates Oxidative Stress-Induced Endothelial Cell Apoptosis in Rats
Hypertension, June 1, 2005; 45(6): 1188 - 1193.
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 Am. J. Physiol. Renal Physiol.Home page
S. Racasan, B. Braam, H. A. Koomans, and J. A. Joles
Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon
Am J Physiol Renal Physiol, April 1, 2005; 288(4): F626 - F636.
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 CirculationHome page
V. Adams, A. Linke, N. Krankel, S. Erbs, S. Gielen, S. Mobius-Winkler, J. F. Gummert, F. W. Mohr, G. Schuler, and R. Hambrecht
Impact of Regular Physical Activity on the NAD(P)H Oxidase and Angiotensin Receptor System in Patients With Coronary Artery Disease
Circulation, February 8, 2005; 111(5): 555 - 562.
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 Arterioscler. Thromb. Vasc. Bio.Home page
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.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Sanz-Rosa, M. P. Oubina, E. Cediel, N. de las Heras, O. Vegazo, J. Jimenez, V. Lahera, and V. Cachofeiro
Effect of AT1 receptor antagonism on vascular and circulating inflammatory mediators in SHR: role of NF-{kappa}B/I{kappa}B system
Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H111 - H115.
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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
C. A. Ruiz-Feria, Y. Yang, and H. Nishimura
Do incremental increases in blood pressure elicit neointimal plaques through endothelial injury?
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1486 - R1493.
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 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J.-M. Li and A. M Shah
Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2004; 287(5): R1014 - R1030.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Benderdour, G. Charron, B. Comte, R. Ayoub, D. Beaudry, S. Foisy, D. deBlois, and C. Des Rosiers
Decreased cardiac mitochondrial NADP+-isocitrate dehydrogenase activity and expression: a marker of oxidative stress in hypertrophy development
Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2122 - H2131.
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 J. Clin. Endocrinol. Metab.Home page
B. Hansel, P. Giral, E. Nobecourt, S. Chantepie, E. Bruckert, M. J. Chapman, and A. Kontush
Metabolic Syndrome Is Associated with Elevated Oxidative Stress and Dysfunctional Dense High-Density Lipoprotein Particles Displaying Impaired Antioxidative Activity
J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 4963 - 4971.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
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.
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 HypertensionHome page
G. S. Jose, M. U. Moreno, S. Olivan, O. Beloqui, A. Fortuno, J. Diez, and G. Zalba
Functional Effect of the p22phox -930A/G Polymorphism on p22phox Expression and NADPH Oxidase Activity in Hypertension
Hypertension, August 1, 2004; 44(2): 163 - 169.
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