Published online before print August 13, 2007, doi: 10.1161/HYPERTENSIONAHA.107.094201
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(Hypertension. 2007;50:600.)
© 2007 American Heart Association, Inc.
Editorial Commentaries |
The Continuing Saga of Neuronal Oxidative Stress in Hypertension
Nox, Nox–Who’s There, and Where?
From the Departments of Internal Medicine and Molecular Physiology and Biophysics and the Cardiovascular Center, University of Iowa Carver College of Medicine, and the Veterans Affairs Medical Center, Iowa City.
Correspondence to Mark W. Chapleau, University of Iowa Carver College of Medicine, 629 MRC, 200 Hawkins Dr, Iowa City, IA 52242. E-mail mark-chapleau{at}uiowa.edu
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Introduction |
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 Top Introduction Is NAD(P)H Oxidase Upregulated...Which Factors Regulate...Does Ganglionic ROS Influence...Implications for Experimental...References |
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Numerous studies have demonstrated increased production of reactive oxygen species (ROS) in blood vessels and kidneys in hypertension and provided evidence that the oxidative stress in these organs causes or contributes to the elevated blood pressure.1,2 Recently, the nervous system has emerged as an additional site and target of oxidative stress in hypertension. The vast majority of these studies have focused on the central nervous system, where activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been shown to contribute to sympatho-excitation and increases in blood pressure.3
NAD(P)H oxidase is a major source of ROS in hypertension, in both peripheral tissues and brain1–3; and homologues of NAD(P)H oxidase (Nox) are differentially expressed in diverse cell types including neurons.3,4 NAD(P)H oxidase consists of 2 membrane-bound subunits (p22phox and Nox) and cytosolic components that are recruited to the membrane during activation (p47phox, p67phox, p40phox, and GTPase Rac).4 Nox homologues include Nox1, Nox2 (gp91phox), Nox3, Nox4, Nox5, Duox1, and Duox2.4
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Is NAD(P)H Oxidase Upregulated in the Peripheral Nervous System in Hypertension? |
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TopIntroductionIs NAD(P)H Oxidase Upregulated...Which Factors Regulate...Does Ganglionic ROS Influence...Implications for Experimental...References |
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Neurohumoral regulation of arterial blood pressure is of course not only determined by the central nervous system but is also influenced by alterations in sensory nerve activity and the function of peripheral sympathetic and parasympathetic nerves. The article by Cao et al,5 published in this issue of Hypertension, is one of a series of articles from this group6–8 that describe NAD(P)H oxidase expression and regulation of ROS production in sympathetic neurons located in prevertebral sympathetic ganglia of normotensive and hypertensive (deoxycorticosterone acetate [DOCA]–salt) rats. The present results confirm earlier findings that Nox1, Nox2, Nox4, p22phox, and p47phox are expressed in sympathetic ganglia7–9 and that NAD(P)H oxidase activity in these ganglia is increased in DOCA-salt hypertension.7
Two important novel findings of this study are that Nox subunits are differentially expressed in sympathetic versus sensory dorsal root ganglia (DRGs) with Nox4 expression being low in DRGs and relatively high in sympathetic ganglia and that NAD(P)H oxidase activity is decreased in hypertensive DRGs, an effect opposite to that seen in sympathetic ganglia5 (see Figure). The decreased oxidase activity in hypertensive DRGs is accompanied by decreases in expression of the regulatory subunits p47phox and Rac1. Conversely, increased NAD(P)H oxidase activity in hypertensive sympathetic ganglia is accompanied by increased expression of p22phox and translocation of p47phox to the membrane (Figure).
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The results underscore the complexity of NAD(P)H oxidase regulation and strongly suggest that not all tissues are subjected to oxidative stress in hypertension despite the fact that they are generally exposed to the high blood pressure and circulating hormones and cytokines known to stimulate ROS production.
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Which Factors Regulate Ganglionic NAD(P)H Oxidase and ROS Production? |
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TopIntroductionIs NAD(P)H Oxidase Upregulated...Which Factors Regulate...Does Ganglionic ROS Influence...Implications for Experimental...References |
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Humoral and Paracrine Factors
NAD(P)H oxidase is activated and/or upregulated by a variety of humoral and paracrine factors including angiotensin II (Ang II), endothelin (ET), growth factors, and cytokines.1–4 ET-1 increases superoxide in prevertebral sympathetic ganglia, an effect mimicked by the ETB receptor agonist sarafotoxin 6c and inhibited by ETB but not ETA receptor antagonists.6–8 Interestingly, high levels of superoxide in sympathetic ganglia of DOCA-salt rats are accompanied by increased expression of ETB receptors in ganglia; ET-1 levels are similar in normotensive and hypertensive ganglia.6 The coupling of ganglionic ROS production to ETB receptor activation contrasts with the predominant role of ETA receptors in generation of ROS in blood vessels. The possibility that other sources of ROS may contribute to ganglionic oxidative stress remains to be determined. The high level of superoxide in sympathetic ganglia from DOCA-salt hypertensive rats was normalized by exposure of ganglia in vitro to the NAD(P)H oxidase inhibitor apocynin, suggesting a major role of NAD(P)H oxidase in generating ganglionic ROS in this model.7
Increased Arterial Pressure
Mechanical stimulation activates NAD(P)H oxidase in blood vessels and cell cultures,4 raising the possibility that increased blood pressure may contribute to activation of the oxidase in hypertension. Intravenous infusion of the 
-adrenergic receptor agonist phenylephrine in normotensive rats increased superoxide in sympathetic ganglia, although the increase was not as large as that observed with an equipressor dose of the ETB receptor agonist sarafotoxin 6c.8 Exposure of ganglia to phenylephrine in vitro did not increase superoxide.8
Studies in my laboratory have recently demonstrated increases in NAD(P)H oxidase expression (Nox2, p22phox, p47phox, and p67phox) and superoxide in sympathetic ganglia of apolipoprotein E–deficient mice with hypercholesterolemia.9 Preliminary results indicate that the high NAD(P)H oxidase expression in the normotensive apolipoprotein E–deficient mice is abrogated by 2-week treatment with the Ang II receptor subtype 1 receptor blocker losartan suggesting that the oxidative stress is not related to blood pressure, per se, but is driven by Ang II. Thus, although increased blood pressure may contribute either directly or indirectly to increased ROS production in sympathetic ganglia in vivo, humoral and paracrine factors, such as ET-1 and Ang II, seem to be the major stimuli for activation and upregulation of ganglionic NAD(P)H oxidase.
Role of Neuronal Versus Nonneuronal Cells
In addition to neurons, sympathetic and sensory ganglia contain nonneuronal cells (eg, glia and fibroblasts) that may express NAD(P)H oxidase. Indeed, earlier studies showed that superoxide is increased in both neuronal and nonneuronal cells in sympathetic ganglia from DOCA-salt hypertensive rats and apolipoprotein E–deficient mice.6,9 Activation of ETB receptors also increases superoxide in both neurons and nonneuronal cells in sympathetic ganglia.6 Future studies are needed to address the relative contributions of neurons versus nonneuronal cells to ganglionic oxidative stress.
NAD(P)H Oxidase in Sensory DRGs
The decrease in NAD(P)H oxidase activity in DRGs from DOCA-salt hypertensive rats presumably reflects low expression of Nox4, p47phox, and Rac1,5 but the underlying mechanism(s) remains obscure. In addition to nonneuronal cells, one must consider the many different types of sensory neurons in DRGs that innervate diverse target tissues and mediate different sensory functions. The expression and regulation of NAD(P)H oxidase may differ in different types of neurons. It will be important to measure gene expression and ROS production in specific types of sensory neurons and assess their functional role, a challenging task indeed. It will also be important to study different models of hypertension with different neurohumoral profiles and investigate responses of DRG neurons to a variety of agonists (eg, ET-1 and Ang II) and antagonists. The possibility of differential expression of endogenous antioxidants in DRGs and sympathetic ganglia should be considered. It is worth noting that ganglionic ROS is also differentially regulated in apolipoprotein E–deficient mice where superoxide is increased in sympathetic ganglia but not affected or decreased in nodose sensory ganglia.9
Reduced NAD(P)H oxidase activity in hypertensive DRG may be compensatory to systemic oxidative stress or hypertension, or, alternatively, it may be detrimental to sensory nerve functions. Clearly, more research is needed.
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Does Ganglionic ROS Influence Sympathetic Nerve Activity and Blood Pressure? |
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TopIntroductionIs NAD(P)H Oxidase Upregulated...Which Factors Regulate...Does Ganglionic ROS Influence...Implications for Experimental...References |
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Antioxidants injected into the brain or delivered via gene transfer attenuate Ang II–induced increases in sympathetic nerve activity (SNA) and arterial pressure and decrease SNA and blood pressure in animal models of hypertension and heart failure.3 Thus, oxidative stress in the central nervous system increases SNA. Available data are consistent with a similar sympatho-excitatory effect of ROS in sympathetic ganglia, but definitive studies have not been performed. Superoxide dismutase catalyzes the conversion of superoxide to hydrogen peroxide, thereby decreasing levels of superoxide. Application of the superoxide dismutase mimetic Tempol to renal postganglionic sympathetic nerve fibers in normotensive rats decreases SNA recorded at a distal site, whereas application of the superoxide dismutase inhibitor diethyldithiocarbamic increases SNA.10 Responses were augmented in spontaneously hypertensive rats10 consistent with the known presence of oxidative stress and increased renal SNA in spontaneously hypertensive rat.
The functional consequences of decreased NAD(P)H oxidase activity in hypertensive DRGs on blood pressure are more difficult to predict. Cao et al5 speculate that decreased NAD(P)H oxidase activity may be associated with reduced synthesis and/or release of vasodilators, such as calcitonin gene-related peptide and NO, from sensory nerve terminals with the potential to contribute to hypertension (Figure). Indeed, antihypertensive actions of sensory neurons in DRGs have been demonstrated. For example, the section of dorsal roots at T9 to L1, designed to selectively denervate afferents innervating the kidney, enhances hypertension induced by a high-sodium diet.11 Consistent with this hypothesis, pharmacological blockade of calcitonin gene-related peptide receptors exacerbates hypertension in several experimental models, including DOCA-salt.12
It is important to recognize that mechanisms other than release of vasodilators from activated sensory nerve terminals may exert antihypertensive actions including reflex inhibition of SNA directed to a variety of target organs important in blood pressure regulation.11 Furthermore, the type of sensory nerve activated will dictate the direction of the reflex change in SNA. In heart failure and renal failure, activation of sensory nerves in DRGs actually contributes to increases in SNA and hypertension.13,14 ROS activate sympatho-excitatory DRG afferents in vivo,15 underscoring the importance of understanding NAD(P)H oxidase regulation in DRG neurons.
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Implications for Experimental and Therapeutic Antioxidant Interventions |
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TopIntroductionIs NAD(P)H Oxidase Upregulated...Which Factors Regulate...Does Ganglionic ROS Influence...Implications for Experimental...References |
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The majority of experimental studies and clinical trials have relied on systemic antioxidant treatments to test the hypothesis that oxidative stress contributes to hypertension and other cardiovascular diseases. The differential expression and regulation of NAD(P)H oxidases in various tissues and types of neurons underscore the need to target antioxidants to specific sites. Furthermore, the varied expression of Nox subunits and limitations in selectivity and efficacy of pharmacological antioxidants encourage more specific tools.
Viral vectors encoding dominant-negative constructs and small interfering RNAs, tissue-specific promoters in transgenic animals, Cre-Lox gene deletion, and novel peptide-based inhibitors are currently being used to selectively inhibit expression of NAD(P)H oxidase subunits in a site- and tissue-specific manner.3,16 Application of these methods to sensory and sympathetic ganglia should prove fruitful in testing new hypotheses raised by the provocative results reported by Cao et al.5
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Acknowledgments |
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Sources of Funding
This work was supported in part from a Department of Veterans Affairs Merit Review Award and National Institutes of Health grant PO1 HL14388.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionIs NAD(P)H Oxidase Upregulated...Which Factors Regulate...Does Ganglionic ROS Influence...Implications for Experimental...References |
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6. Dai X, Galligan JJ, Watts SW, Fink GD, Kreulen DL. Increased O2•- production and upregulation of ETB receptors by sympathetic neurons in DOCA-salt hypertensive rats. Hypertension. 2004; 43: 1048–1054.
7. Dai X, Cao X, Kreulen DL. Superoxide anion is elevated in sympathetic neurons in DOCA-salt hypertension via activation of NADPH oxidase. Am J Physiol Heart Circ Physiol. 2006; 290: H1019–H1026.
8. Lau YE, Galligan JJ, Kreulen DL, Fink GD. Activation of ETB receptors increases superoxide levels in sympathetic ganglia in vivo. Am J Physiol Regul Integr Comp Physiol. 2006; 290: R90–R95.
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Related Article:
Hypertension 2007 50: 663-671.
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