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(Hypertension. 2006;48:482.)
© 2006 American Heart Association, Inc.
Original Articles |
From the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY.
Correspondence to Gang Wang, Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69th St, New York, NY 10021. E-mail gaw2001{at}med.cornell.edu
| Abstract |
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Key Words: arterial hypertension baroreflex calcium channels oxidative stress blood pressure autonomic nervous system
| Introduction |
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Superoxide generated by the enzyme NADPH oxidase has emerged as a key intermediary in the central and peripheral effects of Ang II.10,1416,1821 NADPH oxidase, initially described in neutrophils,22,23 is now known to be present in diverse cell types, including neurons.15,16,2426 NADPH oxidase is composed of membrane-bound subunits, gp91phox and p22phox, and cytoplasmic subunits, p47phox, p40phox, p67phox, and the small GTPase Rac1 and/or Rac2.22,23,2730 The catalytic subunit gp91phox, also termed Nox2, has several homologues, Nox1 and Nox3 through Nox5, the location of which is cell-type specific.22,23 On stimulation of AT1 receptors by Ang II, p47phox is phosphorylated resulting in the assembly of the enzyme and production of superoxide.23,31,32 In some cell types, protein kinase C (PKC) activation via intracellular Ca2+ is a critical step in p47phox phosphorylation and subsequent enzyme assembly.28,33,34
In dmNTS neurons, NADPH oxidase subunits are present in close association with AT1 receptors.25 Furthermore, reactive oxygen species (ROS) scavengers and NADPH oxidase inhibitors attenuate Ang II-elicited enhancement of Ca2+ currents in these neurons.25 These findings have raised the possibility that NADPH oxidase-derived ROS are involved in the effects of Ang II on Ca2+ currents in dmNTS. However, direct evidence linking AT1 receptors to NADPH oxidase-dependent ROS production through intracellular Ca2+ and PKC activation in dmNTS is missing. Furthermore, it is not known whether Nox2 is the catalytic subunit of NADPH oxidase that mediated the ROS production. In the present study, we used ROS imaging, whole-cell patch clamping, and Nox2-null mice to determine whether Ang II induces ROS production in dmNTS neurons and, if so, whether Nox2 plays a role in Ang II-induced ROS production and in the attendant changes in Ca2+ currents.
| Methods |
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Materials
Fluorescent dyes 4-(4-[didecylamino]styryl)- N-methylpyridinium iodide (DiA) and 6-carboxy-2',7'-dichlorodihydro-fluorescein di(acetoxymethyl ester [C-DCDHF-DA]) were purchased from Molecular Probes. Losartan was a gift from Merck and DuPont. Nox2-null mice were obtained from an in-house colony.26,27 C57Bl/6J mice were used as wild-type (WT) controls. The polypeptide gp91ds-tat and its scrambled version35 were synthesized by Bio-Synthesis.
Anterograde Labeling of NTS Neurons Receiving Vagal Afferents
Second-order vagal afferent neurons in the NTS were labeled with DiA in male Sprague-Dawley rats (2 to 4 weeks old) or in the male adult mice, as described previously.25,36,37 Briefly, animals were anesthetized by a mixture of 8 mg/kg of ketamine and 8 mg/kg of xylazine. The right vagus nerve was isolated from the surrounding tissues, and a few crystals of DiA were placed on the nerve at the level of the carotid bifurcation and caudal to the nodose ganglion. The region was sealed with silicone elastomer (World Precision Instruments) to prevent dye leakage.
Dissociation of Second-Order NTS Neurons
Seven to 10 days after labeling, animals were euthanized by CO2, and the brain stem was quickly removed and transferred to a chamber containing ice-cold sucrose-artificial cerebrospinal fluid.25 Coronal slices were obtained and incubated with 0.02% pronase and thermolysin at 36°C in oxygenated lactic acid-containing artificial cerebrospinal fluid.25 Using the area postrema as a landmark, the dmNTS was punched, and neurons were isolated. DiA-labeled presynaptic boutons from first-order neurons, remaining attached to second-order NTS neurons, were identified using a Nikon Diaphot 300 inverted fluorescence microscope. Unlabeled dmNTS neurons were also obtained from the contralateral NTS region of the same animal. The criteria for identification of the unlabeled dmNTS neurons were based on their anatomic location in the dorsomedial portion of the NTS and their typical cell morphology, for example, small round or oval bipolar cells with long thin processes.25,3640
Immunofluorescent Labeling
Dissociated dmNTS neurons were fixed in 4% paraformaldehyde. Neurons were permeabilized, treated with 3% BSA and incubated in a primary antisera mixture including rabbit anti-AT1 receptor (1:100)12,13,25 and goat anti-gp91phox (1:50).25 The neurons were then incubated in a mixture containing anti-rabbit Texas Red and anti-goat fluorescein isothiocyanate antisera (Jackson ImmunoResearch) and were visualized using the Nikon Diaphot 300 microscope.
Detection of Intracellular ROS
ROS production was assessed using C-DCDHF-DA.4143 C-DCDHF- DA loses its diacetate groups by cleavage via intracellular esterases and is oxidized by ROS to dichlorofluorescein (DCF). The isolated neurons were incubated with 5 µmol/L C-DCDHF-DA for 30 minutes. Time-resolved fluorescence was measured every 30 s using IPLab, an image analysis software from Sanalytics Inc. Recordings were started after a stable baseline was achieved. In all of the experiments, concurrent vehicle recordings were performed. No differences in the increase of DCF fluorescence induced by Ang II were observed between the DiA-labeled and DiA-unlabeled neurons selected from the contralateral dmNTS according to morphological criteria. Therefore, in all of the subsequent experiments, results from labeled and unlabeled neurons were pooled.
Electrophysiology
Voltage-gated Ca2+ currents were elicited using the whole-cell configuration of patch clamping.25,39,40,44 An Axopatch-200A patch-clamp amplifier was used with the Cs+ electrode solution.25 Using 2 mmol/L Ca2+ as a charge carrier, Ca2+ currents were elicited by 500-ms pulses from a holding potential of 60 mV to 20 mV using pClamp 8 (Axon Instruments).
Data Analysis
Data are expressed as mean±SEM. Paired or unpaired Student t test was performed. ROS data are expressed as the ratio Ft/Fo, where Ft is fluorescence after the application of Ang II in a given cell, and Fo is the baseline fluorescence of the same cell immediately before application of Ang II. Fo ranged from 105.2 to 169.7 relative fluorescence units. There was no relationship between baseline fluorescence (Fo) and the fluorescence increase induced by Ang II (Ft) under the experimental conditions studied.
| Results |
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Ang II Increases ROS Production and Ca2+ Currents in dmNTS Neurons
We investigated effects of Ang II on ROS production and Ca2+ currents in rat dmNTS neurons. Ang II was applied at concentrations from 3 nmol/L, comparable to endogenous Ang II concentrations in brain tissues.45 In vehicle-treated neurons, DCF fluorescence remained stable during the monitoring period (Figure 1B and 1C). Ang II dose-dependently increased DCF intensity, reflecting an increase in ROS. The effect was initially observed at 3 nmol/L (P<0.05 versus control; n=8) and reached a plateau at 100 nmol/L with an EC50=38.3 nmol/L (Figure 1D). In subsequent studies we tested the effect of Ang II at concentrations of 30 to 100 nmol/L. Ang II (100 nmol/L) was also able to enhance the nifedipine-sensitive L-type Ca2+ current (P<0.05 versus control; n=4; Figure 2). Hydrogen peroxide (2 mmol/L), a product of the dismutation of superoxide by superoxide dismutase, also increased the L-type Ca2+ current in dmNTS neurons (P<0.05 versus control; n=4; Figure 2). Finally, the ROS scavenger Mn (III) porphyrin 5,10,15,20-tetrakis (benzoic acid) porphyrin manganese (III) (MnTBAP)46 (30 µmol/L) blocked the Ang II-induced ROS production (Figure 3A). These observations indicate that nanomolar concentrations of Ang II increase ROS production and Ca2+ currents in dmNTS neurons.
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AT1 Receptors Mediate ROS Production by NADPH Oxidase in dmNTS Neurons
To determine the Ang II receptor subtype47 responsible for the ROS production in rat dmNTS neurons, we examined the effects of the AT1 receptor inhibitor losartan or the AT2 receptor inhibitor PD123319.48 Losartan (3 µmol/L) blocked the Ang II-induced increase in DCF (P>0.05 versus control; n=8), whereas PD123319 (40 µmol/L) did not (Figure 3B). Pretreatment (30 minutes) with the NADPH oxidase assembly inhibitor apocynin (1 mmol/L)49 or the peptide inhibitor gp91ds-tat (1 µmol/L)35 blocked the Ang II-induced increase in DCF (P>0.05 versus control). In contrast, the 1 µmol/L scrambled version of gp91ds-tat had no effect (Figure 3C). These data indicate that Ang II induces ROS production in dmNTS neurons via AT1 receptors and NADPH oxidase.
Nox2 Is Critical for Ang II-Induced Ca2+ Currents and ROS Production in dmNTS Neurons
To obtain direct evidence that Nox2 is involved in Ang II-induced L-type Ca2+ current or superoxide production, we compared Ang II-induced L-type Ca2+ current and ROS production in dmNTS neurons isolated from WT and Nox2-null mice. Ang II significantly potentiated L-type Ca2+ currents of dmNTS neurons in WT mice (P<0.05 versus control; n=4) but not in Nox2-null mice (Figure 4B and 4C). Similarly, Ang II increased DCF intensity in WT mice (P<0.01 versus control; n=6) but not in Nox2-null mice (Figure 4D). These results suggest that the enhancement of both L-type Ca2+ currents and ROS production by Ang II depends on ROS derived from Nox2.
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Ang II-Elicited ROS Production Depends on Intracellular Ca2+ and PKC
To examine the role of intracellular Ca2+ in Ang II-induced ROS production, rat dmNTS neurons were treated continuously with thapsigargin (10 µmol/L) to deplete intracellular Ca2+ stores.50 Pretreatment with thapsigargin (for 30 minutes) partially attenuated the increase in DCF elicited by Ang II (P<0.05 versus control; n=6). Pretreatment with thapsigargin in conjunction with removal of extracellular Ca2+ (for 30 minutes), however, completely blocked the Ang II-induced ROS production (P>0.05 versus control; n=7; Figure 5). To determine whether Ca2+ influx through voltage-gated Ca2+ channels plays a role in the ROS production, we used the L-type Ca2+ channel blocker nifedipine (5 µmol/L) or a combination of N-type Ca2+ channel blocker
-conotoxinGVIA (600 nmol/L) and P/Q-type Ca2+ channel blocker AgaIVA (300 nmol/L). These inhibitors failed to alter the Ang II-mediated increase in DCF (Figure 5). We then examined the role of PKC in the Ang II-induced ROS production. Pretreatment with the PKC inhibitor GF109203X51 (15 µmol/L) abolished the Ang II-induced DCF increase (P>0.05 versus control; n=11; Figure 5). Taken together, these results suggest that intracellular Ca2+ and PKC are involved in the Ang II-induced, Nox2-dependent ROS production in dmNTS neurons.
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| Discussion |
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To measure ROS, we used the ROS-sensitive dye C-DCDHF-DA, which has been thoroughly tested and extensively used in studies of NADPH oxidase-dependent ROS production.4143 C-DCDHF-DA is oxidized by a variety of ROS, including H2O2, peroxynitrite, and superoxide.4143 The validity of the ROS detection method used in the present study is demonstrated by the observations that the DCF signal is blocked by: (1) the ROS scavengers MnTBAP, (2) a NADPH oxidase peptide inhibitor, and (3) constitutive genetic inactivation of Nox2. These observations also rule out the possibility that ROS-independent formation of DCF is attributable, for example, to auto-oxidation of C-DCDHF-DA or conversion of C-DCDHF-DA to DCF by cytochrome c.52
Production of superoxide by NADPH oxidase is dependent on assembly of the cytosolic regulatory subunits with the membrane-bound subunits of the enzyme. A key step in this process is regulated by protein phosphorylation, particularly the PKC-dependent phosphorylation of p47phox.3133 Our finding that a PKC inhibitor blocks Ang II-mediated ROS production in dmNTS neurons suggests that PKC, presumably by phosphorylating p47phox, is essential for the NADPH activation induced by Ang II. We also found that the ROS production evoked by Ang II requires Ca2+, suggesting that the PKC involved is Ca2+ dependent. Concerning the sources of Ca2+, our findings with thapsigargin suggest that Ca2+ release from intracellular stores is needed for the full expression of the ROS increase. An involvement of Ca2+ from intracellular stores is also suggested by the study of Gebke et al,53 who showed in mixed cultures of subfornical organ and organum vasculosum of the lamina terminal neurons that Ang II increases intracellular Ca2+ in the absence of extracellular Ca2+. Furthermore, Sumners et al54 provided evidence that in hypothalamic neurons Ang II induces Ca2+ release from intracellular stores. Although we cannot completely rule out the role of extracellular Ca2+ in the ROS production, Ca2+ influx via voltage-gated Ca2+ channels does not seem to contribute to the ROS production triggered by Ang II. Ang II does activate the L-type Ca2+ channels, but our data suggest that this effect is mediated by Nox2-dependent ROS production.
A previous study in the Neuro-2A cell line showed that the increase in ROS produced by Ang II is not affected by removal of Ca2+.34 This is in contrast to our findings in dmNTS neurons in which Ca2+ was an absolute requirement for the ROS production. The reasons for this discrepancy are not entirely clear. In addition to intrinsic differences between freshly isolated dmNTS neurons and Neuro-2A cells, the Ang II concentration is likely to be an important factor, because higher concentrations of Ang II (2 µmol/L) elicit increases in ROS in dmNTS neurons that are not blocked by Ca2+ removal (Supplemental Figure I, available online at http://hyper.ahajournals.org). Considering that, in the study of Zimmerman et al,34 Ang II was applied at 5 µmol/L, it is conceivable that the discrepancy in the results is because of the difference in Ang II concentration used.
An important consequence of ROS production by Ang II in central autonomic neurons is the resultant increase in intracellular Ca2+ levels.25,34,40,55,56 The present data are consistent with previous reports that the elevation of intracellular Ca2+ induced by Ang II is secondary to the action of ROS on L-type voltage-gated Ca2+ channels.25,34 However, the mechanisms underlying the effects of Nox2-derived ROS on voltage-gated Ca2+ influx remain unclear. One possibility is that oxidative stress modulates voltage-gated Ca2+ channels. Indeed, it is well established that ROS increase voltage-gated Ca2+ currents in neurons.55 Our finding that H2O2 mimics the effect of Ang II on Ca2+ currents in dmNTS neurons supports this possibility, albeit indirectly.
The Ang II-induced potentiation of voltage-gated Ca2+ currents elicited by NADPH oxidase-dependent superoxide production is an important modulator of the excitability of dmNTS neurons.25,39,40 The NTS is a crucial coordinator of cardiorespiratory processes and an important component of the central renin-angiotensin system.15 Within the dmNTS, neurons or glia have been shown to express renin, angiotensinogen, or angiotensin-converting enzyme, as well as Angs I, II, and III and angiotensin AT1 receptors.10 Using dual-labeling immunofluorescence electron microscopy, we demonstrated colocalization of AT1 receptors and Nox2 in single DiA-labeled NTS neurons, indicating that a population of second-order dmNTS sensory neurons contains the AT1 receptor and Nox2.25 Thus, AT1 receptors are located in functional surface membrane sites in Nox2-containing neurons that are contacted by vagal-like and nonvagal afferents in the dmNTS.
Long-term modulation of baroreflex function and disturbances in the renin-angiotensin system are each associated with experimental and clinical hypertension.11,57 The mechanisms mediating adaptations in the baroreflexes presumably involve complex peripheral and central processes in which Ang II plays a role. For example, Ang II-dependent systemic hypertension is associated with increased sympathetic nerve activity,6 whereas Ang II-induced sympathoexcitation has also been linked to NADPH oxidase-derived ROS.1518 Thus, our findings suggest that Ang II-induced ROS production and L-type Ca2+ currents might contribute to the central autonomic effects of Ang II.9,58,59 Moreover, considering the well-established link among L-type Ca2+ channels, ROS, and cellular plasticity,60,61 heightened activation of AT1 receptors in dmNTS neurons may also play a role in the reorganization of autonomic function accompanying hypertension.
Perspectives
The dmNTS is a critical central relay for cardiopulmonary afferents regulating cardiovascular homeostasis. We have demonstrated that Nox2 and AT1 receptors are present in second-order dmNTS neurons in which exposure to Ang II induces ROS production and activation of Ca2+ currents. The Ang II-induced ROS production and Ca2+ currents were not observed in mice lacking Nox2. Furthermore, we have shown that Ang II-dependent ROS production requires intracellular Ca2+ and PKC. The data indicate that Ang II induces ROS production in second-order dmNTS neurons through a Nox2-containing NADPH oxidase. The NADPH oxidase-derived ROS, in turn, activate L-type Ca2+ channels. These findings provide the mechanistic basis for the powerful actions of Ang II in dmNTS and support the concept that ROS derived from Nox2 are critical signaling molecules in central autonomic neurons. They also support the growing evidence that ROS derived from Nox2 play a vital role in both central and peripheral mechanisms of hypertension.
| Acknowledgments |
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This work was supported by the National Institutes of Health grant HL18974.
Disclosures
None.
Received May 30, 2006; first decision June 15, 2006; accepted July 6, 2006.
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S. Lange, J. Heger, G. Euler, M. Wartenberg, H. M. Piper, and H. Sauer Platelet-derived growth factor BB stimulates vasculogenesis of embryonic stem cell-derived endothelial cells by calcium-mediated generation of reactive oxygen species Cardiovasc Res, January 1, 2009; 81(1): 159 - 168. [Abstract] [Full Text] [PDF] |
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G. Wang, T. A. Milner, R. C. Speth, A. C. Gore, D. Wu, C. Iadecola, and J. P. Pierce Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2008; 295(4): R1149 - R1157. [Abstract] [Full Text] [PDF] |
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Q. Zeng, Q. Zhou, F. Yao, S. T. O'Rourke, and C. Sun Endothelin-1 Regulates Cardiac L-Type Calcium Channels via NAD(P)H Oxidase-Derived Superoxide J. Pharmacol. Exp. Ther., September 1, 2008; 326(3): 732 - 738. [Abstract] [Full Text] [PDF] |
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A. G. Teschemacher, S. Wang, M. K. Raizada, J. F.R. Paton, and S. Kasparov Area-Specific Differences in Transmitter Release in Central Catecholaminergic Neurons of Spontaneously Hypertensive Rats Hypertension, August 1, 2008; 52(2): 351 - 358. [Abstract] [Full Text] [PDF] |
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Y. Zhu, P. Fenik, G. Zhan, E. Mazza, M. Kelz, G. Aston-Jones, and S. C. Veasey Selective Loss of Catecholaminergic Wake Active Neurons in a Murine Sleep Apnea Model J. Neurosci., September 12, 2007; 27(37): 10060 - 10071. [Abstract] [Full Text] [PDF] |
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M. Nozoe, Y. Hirooka, Y. Koga, Y. Sagara, T. Kishi, J. F. Engelhardt, and K. Sunagawa Inhibition of Rac1-Derived Reactive Oxygen Species in Nucleus Tractus Solitarius Decreases Blood Pressure and Heart Rate in Stroke-Prone Spontaneously Hypertensive Rats Hypertension, July 1, 2007; 50(1): 62 - 68. [Abstract] [Full Text] [PDF] |
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Q. Chen and H.-L. Pan Signaling Mechanisms of Angiotensin II-Induced Attenuation of GABAergic Input to Hypothalamic Presympathetic Neurons J Neurophysiol, May 1, 2007; 97(5): 3279 - 3287. [Abstract] [Full Text] [PDF] |
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