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(Circulation. 2003;107:1053.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Endothelin-1 Increases Vascular Superoxide via Endothelin_A–NADPH Oxidase Pathway in Low-Renin Hypertension

Lixin Li, MD; Gregory D. Fink, PhD; Stephanie W. Watts, PhD; Carrie A. Northcott, MS; James J. Galligan, PhD; Patrick J. Pagano, PhD; Alex F. Chen, MD, PhD

From the Department of Pharmacology and Toxicology (L.L., G.D.F., S.W.W., C.A.N., J.J.G, A.F.C.) and the Neuroscience Program (G.D.F., J.J.G, A.F.C.), Michigan State University, East Lansing; and the Hypertension and Vascular Research Division (P.J.P.), Henry Ford Hospital, Detroit, Mich.

Correspondence to Alex F. Chen, MD, PhD, FAHA, Department of Pharmacology and Toxicology, B403 Life Sciences Building, Michigan State University, East Lansing, MI 48824-1317. E-mail chenal{at}msu.edu

	Abstract

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Background— Angiotensin II–induced hypertension is associated with NAD(P)H oxidase–dependent superoxide production in the vessel wall. Vascular superoxide level is also increased in deoxycorticosterone acetate (DOCA)–salt hypertension, which is associated with a markedly depressed plasma renin activity because of sodium retention. However, the mechanisms underlying superoxide production in low-renin hypertension are undefined.

Methods and Results— This study investigated (1) whether and how endothelin-1 (ET-1), which is increased in DOCA-salt hypertensive rats, contributes to arterial superoxide generation and (2) the effect of gene transfer of manganese superoxide dismutase and endothelial nitric oxide synthase. Both superoxide and ET-1 levels were significantly elevated in carotid arteries of DOCA-salt rats compared with that of the sham-operated controls. ET-1 concentration-dependently stimulated superoxide production in vitro in carotid arteries of normotensive rats. The increase in arterial superoxide in both ET-1–treated normotensive and DOCA-salt rats was reversed by a selective ET_A receptor antagonist, ABT-627, the flavoprotein inhibitor diphenyleneiodonium, and the NADPH oxidase inhibitor apocynin but not by the nitric oxide synthase inhibitor N-L-arginine methyl ester or the xanthine oxidase inhibitor allopurinol. Furthermore, in vivo blockade of ET_A receptors significantly reduced arterial superoxide levels, with a concomitant decrease of systolic blood pressure in DOCA-salt rats. Ex vivo gene transfer of manganese superoxide dismutase or endothelial nitric oxide synthase also suppressed superoxide levels in carotid arteries of DOCA-salt rats.

Conclusions— These findings suggest that ET-1 augments vascular superoxide production at least in part via an ET_A/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.

Key Words: endothelin • NADPH oxidase • superoxide • hypertension

	Introduction

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Oxidative stress and the inactivation of nitric oxide (NO) by vascular superoxide anion (O₂^-) play a critical role in the pathogenesis of vascular disease, including hypertension.^1,2 Arterial O₂^- is elevated in angiotensin II (Ang II)–induced hypertension,³ attributable to a large extent to NADPH oxidase activation by Ang II.^4,5 However, an excess of vascular O₂^- production has also been found in deoxycorticosterone acetate (DOCA)–salt hypertension,^6–9 a model with a markedly depressed plasma renin activity because of sodium retention.¹⁰ Humoral mechanisms responsible for O₂^- production in mineralocorticoid hypertension remain to be delineated.

In contrast to Ang II–induced hypertension, endothelin-1 (ET-1) has been shown to contribute to the pathogenesis of salt-sensitive hypertension in animals and humans,¹¹ secondary to a low-renin state.^12,13 ET-1 may be one of the most potent vasoconstrictors produced in the blood vessel wall to date.¹⁴ We have now found that the level of ET-1 is increased in the arteries of DOCA-salt hypertensive rats. The vasoactive effects of ET-1 are mediated through 2 receptor types, ET_A and ET_B.¹⁵ ET_A receptors play an important role in the development of DOCA-salt–induced hypertension, whereas ET_B receptors may protect against vascular and renal injuries in this model.¹⁶ ET-1 is able to activate NADPH oxidase in endothelial cells¹⁷ and stimulates O₂^- production in pulmonary smooth muscle cells.¹⁸ Therefore, we hypothesized that ET-1 activates NADPH oxidase to produce vascular O₂^- in DOCA-salt hypertensive rats. Our results suggest that ET-1 produces O₂^- via an ET_A-NADPH oxidase pathway in carotid arteries of normotensive and DOCA-salt hypertensive rats. Because recent studies have suggested that endothelial NO synthase (eNOS) may also contribute to O₂^- production when its essential cofactor BH4 is below the optimal level (ie, "uncoupled" eNOS),² we used eNOS gene transfer in the present study in addition to NOS inhibition to distinguish the sources of O₂^- generation. Gene transfer of manganese superoxide dismutase (MnSOD) was also used to test the hypothesis that mitochondria may be a key source for O₂^- formation. Our data indicate that local expression of these recombinant proteins significantly reduced vascular O₂^- levels.

	Methods

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DOCA-Salt Hypertensive Rats and In Vivo Pharmacological Intervention
DOCA-salt hypertension was created in adult male Sprague-Dawley rats as previously described.^9,19 Starting at week 3, some of the DOCA-salt rats received ABT-627 (Abbott Laboratories), a selective ET_A receptor antagonist, 2 mg · kg body wt^-1 · d^-1 in drinking water for 2 weeks.²⁰ Blood pressure was measured in conscious rats by the noninvasive tail-cuff method. The vessels were collected between weeks 4 and 5 after DOCA implantation. Animal procedures were in accordance with the institutional guidelines of the Michigan State University.

Ex Vivo Gene Transfer
The preparation of adenoviral vectors was as described.^9,21,22 Isolated arterial segments (4 mm) were transduced without (negative control) or with adenoviral vectors encoding eNOS, MnSOD, or ß-galactosidase (ß-gal) gene (positive control) at 5x10¹⁰ plaque formation units (pfu)/mL in minimal essential medium at 37°C for 4 hours, followed by incubation in fresh medium for 24 hours.⁹

Vascular O₂^- Levels
Vascular O₂^- was assayed with oxidative dihydroethidium fluorescence and lucigenin (5 µmol/L) chemiluminescence.^9,23 To determine the effects of ET-1, ET_A receptor, flavoprotein, NADPH oxidase, xanthine oxidase, and NOS-mediated O₂^- production, arterial segments (4 mm) were preincubated at 37°C with ET-1 (0.01 to 1 nmol/L, 4 hours), ABT-627 (30 nmol/L, 60 minutes), diphenyleneiodonium (DPI, 0.1 mmol/L, 30 minutes), apocynin (0.1 mmol/L, 60 minutes), allopurinol (1 µmol/L, 60 minutes), or N-L-arginine methyl ester (L-NAME, 0.1 mmol/L/L, 60 minutes), respectively. Arteries transduced with MnSOD, eNOS, and ß-gal (0 or 5x10¹⁰ pfu/mL) or collected after 2-week in vivo ABT-627 treatments were also assayed for O₂^- levels.

ET-1 Immunoassay
Vascular ET-1 levels were determined by a chemiluminescence-based immunoassay with a commercial kit (R&D Systems). Briefly, arteries from sham, DOCA, or normal rats treated with ET-1 were frozen in liquid nitrogen, homogenized in 1 mol/L acetic acid (1 mL/50 mg tissue) containing 1.5x10^-5 mol/L pepstatin, and immediately boiled for 10 minutes. After being chilled, the homogenate was centrifuged at 20 000g for 30 minutes at 4°C, and the supernatant was assayed for ET-1 content.

Data Analysis
Data were expressed as mean±SEM. Repeated-measures ANOVA was used for comparison of multiple values obtained from the same subject, whereas factorial ANOVA was used for comparing data obtained from 2 independent samples of subjects. Bonferroni’s procedure was used to control type I error. A value of P<0.05 was considered significant.

	Results

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ET-1 Levels in Carotid Arteries of DOCA-Salt Rats and Normal Rats After ET-1 Treatment
ET-1 levels in carotid arteries were significantly higher in DOCA-salt rats than in sham controls. Similarly, ET-1 levels in arteries of normal rats treated with ET-1 for 4 hours were also significantly increased compared with the vessels without ET-1 treatment. Arterial ET-1 content in DOCA-salt rats was comparable to that of arteries of normal rats treated with ET-1 for 4 hours at 10^-9 mol/L (Figure 1, n=4 to 6, **P<0.01 versus control, ##P<0.01 versus sham).

View larger version (18K): [in this window] [in a new window]   Figure 1. Elevated ET-1 levels in carotid arteries of DOCA-salt rats. ET-1–treated carotid arteries of normal rats or carotid arteries of sham or DOCA-salt rats were subjected to ET-1 assay with a commercial enzyme immunoassay kit. n=4 to 6; **P<0.01 vs control, ##P<0.01 vs sham.

Effect of ET-1 on O₂^- Production in Carotid Arteries of Normal Rats
Arterial O₂^- levels of normal rats were increased in a concentration-dependent manner after incubation for 4 hours with ET-1, and pretreatment of ABT-627 (3x10^-8 mol/L), a selective ET_A receptor antagonist, completely reversed the effect of ET-1 on O₂^- production (Figure 2, n=5 to 6, *P<0.05 and **P<0.01 versus control, #P<0.05 versus 10^-9 mol/L ET-1 treated group).

View larger version (25K): [in this window] [in a new window]   Figure 2. Effect of ET-1 on O2- production in carotid arteries of normal rats. All vessel segments were incubated at 37°C for 4 hours without (control) or with ET-1 at increasing concentrations. +ABT627 indicates that this group was incubated with ABT-627 (3x10-8 mol/L) for 1 hour before ET-1 treatment. All vessel segments were subjected to O2- measurement by lucigenin-enhanced chemiluminescence assay (see Methods). n=5 to 6; *P<0.05 and **P<0.01 vs control, #P<0.05 vs 10-9mol/L ET-1–treated group.

In Vivo Blockade of ET_A Receptors on Blood Pressure and Arterial O₂^- Levels in DOCA-Salt Rats
There was a significant increase in average systolic blood pressure (Figure 3A, 176±4 versus 117±2 mm Hg, n=5, **P<0.01) and arterial O₂^- levels (Figure 3B, *P<0.05 versus sham; see also Figure 6, E and F) in DOCA-salt rats compared with sham controls. In vivo blockade of ET_A receptors for 2 weeks with ABT-627 significantly lowered blood pressure in DOCA-salt rats (Figure 3A, n=5, #P<0.05), with a concomitant decrease in arterial O₂^- levels in the same group of DOCA-salt rats (Figure 3B, n=5, #P< 0.05 versus DOCA).

View larger version (38K): [in this window] [in a new window]   Figure 3. A, Effect of ABT-627 (2 mg · g body wt-1 · d-1) on average systolic blood pressure in DOCA-salt rats (n=5; **P<0.01 vs sham rats, #P< 0.05 vs DOCA-salt rats). B, Effect of ABT-627 (2 mg · kg body wt-1 · d-1) on O2- production in carotid arteries of DOCA-salt rats. Isolated arterial segments of sham, DOCA-salt, or ABT-627–treated DOCA-salt rats were subjected to O2- assay. n=5 to 6; *P< 0.05 vs sham, #P< 0.05 vs DOCA-salt group and P>0.05 vs sham.

View larger version (17K): [in this window] [in a new window]   Figure 6. Fluorescent confocal micrographs showing in situ O2- detection in rat carotid arteries. Arterial sections were labeled with oxidative dye dihydroethidium, which fluoresces red when oxidized to ethidium bromide by superoxide (see Methods). A through D, Carotid arteries from normal rats: (A) control, (B) ET-1 treatment, (C) ABT-627 followed by ET-1 treatment, and (D) DPI followed by ET-1 treatment. E through J, Carotid arteries of DOCA-salt or sham rats: (E) sham, (F) DOCA-salt, (G) in vitro DPI-treated DOCA-salt, (H) in vivo ABT-627–treated DOCA-salt, (I) MnSOD gene–transferred DOCA-salt, and (J) eNOS gene–transferred DOCA-salt. Sections shown are typical of 3 separate experiments. Bar=0.05 mm.

Role of NADPH Oxidase, NOS, and Xanthine Oxidase on Arterial O₂^- Levels
DPI (10^-4 mol/L), a flavoprotein inhibitor, and apocynin (10^-4 mol/L), a selective NADPH oxidase inhibitor, significantly reduced arterial O₂^- levels in DOCA-salt rats (Figure 4; see also Figure 6G). In contrast, allopurinol (10^-6 mol/L) had no effect, and L-NAME (10^-4 mol/L) increased arterial O₂^- levels. Furthermore, both DPI and apocynin but not allopurinol significantly attenuated O₂^- levels in arteries of normal rats treated with ET-1 (10^-9 mol/L) (Figure 4, n=5 to 8, *P<0.05 and **P<0.01 versus control).

View larger version (21K): [in this window] [in a new window]   Figure 4. Role of NADPH oxidase on O2- production. Treatment with apocynin or DPI (10-4 mol/L) inhibited O2- production in carotid arteries of DOCA-salt rats and in ET-1–treated (10-9 mol/L) carotid arteries of normal rats. Treatment with allopurinol (10-6 mol/L) had no significant effect on arterial O2- levels, whereas treatment with L-NAME (10-4 mol/L) increased O2- levels. n=5 to 8; *P< 0.05 and **P<0.01 vs control.

Gene Transfer of eNOS and MnSOD on O₂^- Levels in Carotid Arteries of DOCA-Salt Rats
Arterial segments from sham or DOCA-salt rats were transduced with adenoviral vectors encoding eNOS, MnSOD, or ß-gal for 4 hours at titers of 0 (control) and 5x10¹⁰ pfu/mL and then transferred to fresh medium overnight before O₂^- assay.⁹ Ex vivo gene transfer of either MnSOD or eNOS significantly decreased the arterial O₂^- levels in DOCA-salt rats compared with the nontransduced controls of DOCA-salt rats that underwent the same medium incubation for 24 hours. In contrast, gene transfer of ß-gal had no effect on O₂^- levels (Figure 5, n=4 to 8, *P<0.05 versus DOCA, #P<0.05 versus sham).

View larger version (26K): [in this window] [in a new window]   Figure 5. Effect of gene transfer of MnSOD or eNOS on O2- production in carotid arteries of DOCA-salt rats. Isolated carotid arteries of sham or DOCA-salt rats were transduced with adenoviral vectors encoding eNOS, MnSOD, or ß-gal for 4 hours at titers of 0 (control) and 5x1010 pfu/mL and then transferred to fresh medium overnight before O2- assay. n=4 to 8; *P<0.05 vs DOCA, #P<0.05 vs sham.

In Situ Detection of Vascular Superoxide
In the presence of the superoxide-sensitive dye dihydroethidium, the ethidium bromide (EtBr) fluorescence (ie, red color) was markedly higher throughout the vessel wall of the ET-1–treated arteries of normal rat (Figure 6B) and arteries of DOCA-salt rats (Figure 6F) compared with the vessels from normal rats (Figure 6A) and sham rats (Figure 6E). The superoxide fluorescent intensity was dramatically suppressed in the arteries of DOCA-salt rats treated with DPI in vitro (Figure 6G) and arteries of DOCA-salt rats treated with ABT-627 for 2 weeks in vivo (Figure 6H) compared with the vessels from the control DOCA-salt rats (Figure 6F). Gene transfer of MnSOD (Figure 6I) and eNOS (Figure 6J) attenuated EtBr fluorescence in arteries of DOCA-salt rats. Both ABT-627 (Figure 6C) and DPI (Figure 6D) also suppressed the EtBr fluorescence in ET-1–treated arteries of normal rats.

	Discussion

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The major new findings of this study are that ET-1 stimulates O₂^- production, via an ET_A/NADPH oxidase pathway, in carotid arteries of DOCA-salt hypertensive rats and that in vivo ET_A receptor blockade attenuates systolic blood pressure and arterial O₂^- levels. In addition, gene transfer of MnSOD or eNOS significantly reduces the increased arterial O₂^- levels in this low-renin hypertension model.

Arterial superoxide levels are markedly increased in DOCA-salt hypertensive rats.^6–9 However, it was not clear which factors are responsible for the augmented superoxide production. It is well known that ET-1 plays an important role in DOCA-salt hypertension. ET-1 is implicated in the development and maintenance of hypertension at least in part because of its potent vasoconstrictor property.^11–13 Our results demonstrate that there was a much higher ET-1 level in carotid arteries of DOCA-salt rats than in sham controls, an observation that is consistent with published studies showing enhanced vascular mRNA expression and ET-1 contents in the resistance arteries of this hypertension model.¹⁴ Furthermore, our data suggest that arterial ET-1 levels in DOCA-salt hypertensive rats were comparable to those observed in the normal arteries treated with 10^-9 mol/L of ET-1 from normal rats.

It was recently reported that ET-1 activates NADPH oxidase and induces superoxide production in cultured endothelial and smooth muscle cells.^17,18 Convincing evidence indicates that the major enzymatic sources for vascular superoxide formation are NADPH oxidase, xanthine oxidase, and uncoupled NOS.² In DOCA-salt hypertensive rats, aortic NADPH oxidase activity was significantly increased compared with their normotensive controls.^7,8 In the present study, we examined (1) the effect of ET-1 on superoxide production both in vitro in normal rats and in vivo in DOCA-salt hypertensive rats and (2) whether this effect is mediated by NADPH oxidase, xanthine oxidase, or uncoupled NOS. Our results indicate that (1) ET-1 stimulates arterial O₂^- production in a concentration-dependent manner in normal rats; (2) apocynin but not L-NAME or allopurinol inhibits the O₂^- production in both ET-1–stimulated arteries of normal rats and arteries of DOCA-salt rats; and (3) the selective ET_A receptor antagonist ABT-627 suppresses superoxide production in vitro in ET-1–treated arteries of normal rats and in vivo in arteries of DOCA-salt hypertensive rats. Collectively, these data suggest that ET-1 stimulates arterial O₂^- production in DOCA-salt hypertension, and NADPH oxidase but not xanthine oxidase or uncoupled NOS may play a major role in O₂^- production in this model. The selectivity of apocynin, a methoxy-substituted catechol, on NADPH oxidase has been well characterized, because it impedes the assembly of the p47phox and p67phox subunits within the membrane NADPH oxidase complex.^8,24

There are at least 2 vascular ET-1 receptors, ET_A and ET_B.¹⁵ ET-1 exerts its vasoactive effects mainly through the activation of the G protein–coupled ET_A receptors on vascular smooth muscle cells,¹⁶ whereas ET_B may exert protective effects in DOCA-salt hypertension.^16,25 There is an exaggerated vascular and renal injury in ET_B receptor–deficient rats of DOCA-salt hypertension, and such injuries were significantly improved after the treatment with ABT-627, a selective ET_A receptor antagonist.²⁵ In the present study, we demonstrated that arterial O₂^- levels were increased significantly in DOCA-salt rats compared with the sham controls, an effect that was reversed after in vivo ABT-627 treatment in DOCA-salt rats, with a concomitant reduction of blood pressure. These findings are consistent with recent studies showing that O₂^- production in rebound pulmonary hypertension was mediated by ET_A receptors¹⁸ and that tempol, a superoxide scavenger, normalized blood pressure in spontaneously hypertensive rats.²⁶ However, it is important to note that although in vivo blockade of ET_A receptors by ABT-627 for 2 weeks suppressed the arterial O₂^- to control levels, the blood pressure was only partially reduced. These results suggest that ET_A receptor–mediated activation of NADPH oxidase by ET-1 is only one of the contributing factors for the O₂^--induced blood pressure increase in this model of hypertension. In addition, they also suggest that the reduced vascular O₂^- levels were only partially responsible for decreasing blood pressure and that in vivo ET_A receptor blockade may also result in reduced smooth muscle tension. Furthermore, the possible influence of ET_B receptors on ET-1–induced O₂^- production in arteries and veins is not clear and is a subject currently being investigated. Finally, it is also of interest to note that hypertension per se may not be a major stimulus for augmented vascular superoxide because norepinephrine-induced hypertension is not associated with an increase in vascular superoxide levels.⁴ Thus, O₂^- production may be a result of the effects of different vasoactive agents in different types of hypertension. Although Ang II is clearly a key stimulus of vascular O₂^- production in high-angiotensin hypertension, ET-1 may play a major role for increasing vascular O₂^- in low-renin hypertension, such as the DOCA-salt model.

Several pathophysiological conditions in addition to hypertension have been associated with increased superoxide production. These include atherosclerosis, hypercholesterolemia, diabetes, and heart failure; cigarette smoking has also been implicated.⁴ In most of these cases, the increase in vascular O₂^- has been shown to impair endothelium-dependent NO-mediated vascular relaxation by inactivating endogenous NO.⁴ In addition, superoxide has also been shown to affect the sensitivity of blood vessels to vasodilators,²⁷ and it triggers expression of vascular adhesion molecules and vascular remodeling.⁹ The reaction rate between O₂^- and NO is linear and extremely rapid.²⁸ For this reason, the local balance between O₂^-, NO, and SOD in the vascular wall is dynamic, and relatively minor changes in the levels of any of these factors may substantially alter vascular tone. Localized gene transfer to the vessel wall may be an effective means of increasing NO and/or reducing O₂^- levels. Indeed, our results demonstrate that gene transfer of MnSOD or eNOS significantly reduced arterial O₂^- levels in DOCA-salt hypertensive rats. We chose MnSOD for vascular gene transfer because (1) our recent study indicates that endogenous MnSOD is significantly reduced in the carotid arteries of DOCA-salt hypertensive rats and that gene transfer of MnSOD restored the functional capacity of the antioxidant enzyme in scavenging elevated O₂^-9 and (2) mitochondria may be a major location in which vascular O₂^- is produced.²⁹ In agreement with our findings, gene transfer of MnSOD has been shown to normalize superoxide-induced impairment of endothelium-dependent relaxation,^30,31 whereas gene transfer of cytosolic Cu/Zn-SOD or extracellular SOD did not.^32–34 Conversely, recent studies have demonstrated that both ex vivo and in vivo gene transfer of eNOS or nNOS restored NO-mediated arterial relaxation, which was impaired by increased O₂^- in hypertensive,^34,35 atherosclerotic,^{31,33,36–38} or diabetic animals.^30,39 Furthermore, in vivo gene transfer of eNOS to spontaneously hypertensive rats has resulted in direct blood pressure reduction.⁴⁰ Consistent with these studies, our data showed that gene transfer of eNOS significantly decreased O₂^- levels in carotid arteries in DOCA-salt rats. Taken together, these experimental observations support the novel concept that NO generated by recombinant NOS, as a result of vascular gene transfer, provides an effective means of inactivating O₂^- and thereby improving vasomotor function.

In conclusion, the present study demonstrates that ET-1 is a potent stimulus for arterial O₂^- produced in low-renin DOCA-salt hypertension, an effect that is at least partially mediated by the ET_A receptor/NADPH oxidase pathway. Vascular gene transfer of MnSOD and eNOS is an effective strategy in reducing O₂^- levels in this model. These findings may provide a mechanistic basis for therapeutic interventions aimed at reducing superoxide-induced vascular dysfunctions associated with increased ET-1 levels in low-renin hypertension.

	Acknowledgments

 
This work was supported in part by the American Heart Association, grants 9806347X and 0130537Z; the American Diabetes Association, research award 7-01-RA-10; and the Juvenile Diabetes Research Foundation, innovative grant 5-2001-311 (to Dr Chen). Dr Li is an awardee of the AHA/Midwest Affiliate Physician-Scientist Postdoctoral Fellowship (0225408Z).

Received September 26, 2002; revision received November 7, 2002; accepted November 8, 2002.

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