Published online before print August 27, 2007, doi: 10.1161/HYPERTENSIONAHA.107.096057
(Hypertension. 2007;50:643.)
© 2007 American Heart Association, Inc.
Original Articles |
Carbon Monoxide Stimulates the Ca2+–Activated Big Conductance K Channels in Cultured Human Endothelial Cells
From the Department of Pharmacology (D.-L.D., B.-F.Y.), Harbin Medical University, Harbin, China; and the Departments of Pharmacology (D.-L.D., Y.Z., D.-H.L., A.N., W.-H.W.) and Medicine (J.C., S.P., M.S.G.), New York Medical College, Valhalla, NY.
Correspondence to Wen-Hui Wang, Department of Pharmacology, New York Medical College, Valhalla, NY 10595. E-mail wenhui_wang{at}nymc.edu
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Abstract |
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We used the whole-cell patch-clamp technique to study K channels in the human umbilical vein endothelial cells and identified a 201 pS K channel, which was blocked by tetraethylammonium and iberiotoxin but not by TRAM34 and apamin. This suggests that the Ca2+-activated big-conductance K channel (BK) is expressed in endothelial cells. Application of carbon monoxide (CO) or tricarbonylchloro(glycinato)ruthenium(II), a water soluble CO donor, stimulated the BK channels. Moreover, application of hemin, a substrate of heme oxygenase, mimicked the effect of CO and increased the BK channel activity. The stimulatory effect of hemin was significantly diminished by tin mesoporphyrin, an inhibitor of heme oxygenase. To determine whether the stimulatory effect of CO on the BK channel was mediated by NO and the cGMP-dependent pathway, we examined the effect of CO on BK channels in cells treated with, NG-nitro-L-arginine methyl ester, 1H(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, an inhibitor of soluble guanylate cyclase, or KT5823, an inhibitor of protein kinase G. Addition of either diethylamine NONOate or sodium nitroprusside significantly increased BK channel activity. Inhibition of endogenous NO synthesis with NG-nitro-L-arginine methyl ester, blocking soluble guanylate cyclase or protein kinase G, delayed but did not prevent the CO-induced activation of BK channels. Finally, application of an antioxidant agent, ebselen, had no effect on CO-mediated stimulation of BK channels in human umbilical vein endothelial cells. We conclude that BK channels are expressed in human umbilical vein endothelial cells and that they are activated by both CO and NO. CO activates BK channels directly, as well as via a mechanism involving NO or the cGMP-dependent pathway.
Key Words: heme oxygenase • NO • cGMP • reactive oxygen species • K channel
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Introduction |
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An important role is played by Ca2+-activated K channels in determining the cell membrane potential in endothelial cells.1,2 Because the cell membrane potential provides an important driving force for Ca2+ entry through Ca2+-permeable channels, such as the transient receptor potential channel,3 alteration in the membrane potential is expected to affect the Ca2+ influx4and NO formation in endothelial cells.5 Thus, Ca2+-activated K channels in endothelial cells are involved in mediating endothelium-dependent dilation of vessels6 and in shear stress-induced vasodilation.7 Three types of Ca2+-activated K channels, the small-conductance K, intermediate-conductance K, and big-conductance K (BK),1 have been identified with the patch clamp technique and molecular biological approaches in endothelial cells. It is generally established that Ca2+-activated K channels are mainly responsible for the hyperpolarization induced by vasoactive substances, including acetylcholine.1 For instance, it has been reported that deletion of the intermediate-conductance K channel impairs the vasodilation induced by endothelial-derived hyperpolarization factor.6 Also, increased small-conductance K channel activity is correlated with sustained hyperpolarization in endothelial cells of the arteries.2 Because BK channels have a high channel conductance, it is conceivable that they could play an important role in participating in generating the membrane potential in endothelial cells when BK channels are activated. Indeed, it has been shown that expression of BK channels in cultured endothelial cells caused a transient hyperpolarization induced by ATP.8 However, the regulatory mechanism of BK channels in endothelial cells and their role in the regulation of endothelial cell function are largely unknown. In contrast, BK channels in smooth muscle cells are intensively studied. It has been reported that BK channels in smooth muscle cells are activated by NO, cGMP, and epoxyeicosatrienoic acid and inhibited by 20-hydroxyeicosatetraenoic acid.9–12 Recently, a large body of evidence has shown that carbon monoxide (CO) can also dilate arterioles by stimulating BK channel activity in smooth muscle cells.13,14 We speculate that CO may also activate BK channels in endothelial cells. Thus, the aim of the present study is to test the possibility that CO plays an important role in determining the BK channel activity in endothelial cells.
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Methods |
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Endothelial Cell Culture
Human umbilical vein endothelial cells (HUVECs) were purchased from Cambrex Bio Science Inc and were cultured with 5% CO2 at 37°C in endothelial cell medium-2 (ECM-2) medium obtained from the same company. We used endothelial cells between passages 5 to 8 for patch-clamp experiments. The cells were placed on a 5x5-mm cover glass, which was transferred to a chamber (1 mL) mounted on the stage of a Nikon inverted microscope before the experiments.
Western Blot and Patch Clamp Experiments
We followed the methods described previously to conduct Western blot analysis and patch clamp experiments.15,16 Detailed methods are described in the an online data supplement available at http://hyper.ahajournals.org.
Experimental Solution
In addition to the normal bath solution composed of (in millimoles per liter) 138 NaCl, 5 KCl, 0.5 MgCl2, 1.5 CaCl2, and 10 HEPES (pH 7.4), a high K bath solution was used containing (in millimoles per liter) 138 KCl, 0.5 MgCl2, 1.5 CaCl2, and 10 HEPES (pH 7.4). We also added 0.1 mmol/L of niflumic acid to the bath to block possible Cl– channels. Niflumic acid at concentrations used in the present study did not affect BK channel activity. We used 2 types of pipette solutions: Ca2+-containing and Ca2+-free solution. The Ca2+-containing pipette solution (3.6 µmol/L) was composed of (in millimoles per liter) 138 KCl, 4 MgCl2, 0.955 CaCl2, 1 EGTA, and 5 HEPES (pH 7.2). The same Ca2+ concentrations have been used to study BK channels by other investigators.17
Chemicals and Statistics
Tin mesoporphyrin (SnMP) was purchased from Frontier Scientific, Inc. Tricarbonylchloro(glycinato)ruthenium(II) (CORM3), a CO donor,18 was synthesized in Dr John Falck’s laboratory at Southwestern Medical Center, University of Texas, and dissolved in water. To prepare SnMP stock solution (4 mmol/L), the chemical was dissolved in 5 mmol/L of Na2CO3. Hemin (2 mmol/L) was dissolved in 8 mmol/L of (2-amino-2-chydroxymethyl)-1,3-propanediol (Tris) and 100 mmol/L of NaOH solution, vortexed, and followed by adding deionized water. The pH value of the stock solution of hemin was titrated to 7.8 using HCl, and the solution was further subjected to sonication and filtration with a 0.8-µm filter. For the preparation of CO stock solution, we followed the method published previously. Briefly, the bath solution in a sealed glass tube was bubbled with pure CO gas for 15 minutes, and the final concentration of CO in the tube was estimated to be 1 mmol/L, as reported previously.19 All of the other chemicals applied in the present study were purchased from Sigma-Aldrich. Data are presented as mean±SEM, and significance was determined using Student t test or 1-way ANOVA, followed by Tukey’s test. P<0.05 was considered significant.
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Results |
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BK Channels Are Expressed in HUVECs
We first used the whole-cell patch clamp configuration to explore BK channel activity in HUVECs. After forming a high-resistance seal, the endothelial cell was ruptured and clamped at +50 mV (depolarization), because it activates BK channels. Figure 1A is a channel recording showing the activity of the BK channels with 138 mmol/L of KCl and 3.6 µmol/L of Ca2+ in the pipette (intracellular solution) in the endothelial cells bathed either in high KCl solution (138 mmol/L; top set of the trace) or in 5 mmol/L KCl-containing solution (bottom set of the trace). Figure 1B is a current and voltage curve of the BK channel, which yields a slope conductance of 201±6 pS (n=11) with a symmetric high KCl solution and 90±7 pS (n=11) with 138 mmol/L of KCl in the pipette and 5 mmol/L of KCl in the bath solution. From inspection of the channel recording, it is apparent that the channel activity increased by depolarization. Data summarized in Figure 1C shows that a 5.7±0.5-mV (n=7) depolarization doubled BK channel activity.
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) in the bath solution, respectively. C is a typical curve fitting showing the relationship between voltage and channel activity defined by NPo. The channel activity was recorded with a whole-cell patch clamp, and the holding potential (cell membrane potential) is indicated on the top of the each trace. The channel close level (0) is indicated by a short dotted line.To further confirm that the 201 pS K channel is a BK channel in the endothelial cells, we examined the channel activity in the presence of apamin (2 µmol/L; a specific blocker of the small-conductance K channel) or 2 µmol/L of TRAM-34 (a selective blocker of the intermediate-conductance K channel).20 It is apparent that neither apamin (Figure 2A) nor TRAM34 (Figure 2B) had an effect on BK channel activity. In contrast, the K channel activity was inhibited by 0.8 mmol/L of tetraethylammonium (TEA), a nonspecific BK channel inhibitor. Figure 2C is a channel recording showing that TEA decreased NPo (a product of channel number [N] and open probability [Po]) and apparent channel current amplitude by 80%. Figure 2D shows that 100 nmol/L of iberiotoxin, a specific BK channel inhibitor, decreased NPo without changing the current amplitude. Data summarized in Figure 2E demonstrate that application of TEA (n=5) or iberiotoxin (n=5) almost completely inhibited K channel activity. Also, the inhibitory effect of TEA and iberiotoxin was fully reversible, because washout restored the channel activity. Thus, we confirmed the previous finding that BK channel is expressed in endothelial cells.21,22
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CO Stimulates BK in HUVECs
We next examined the effect of CO on BK channel activity using the whole-cell recording technique. Figure 3A is a recording showing the effect of 3 µmol/L of CO on BK channels in an endothelial cell that was clamped at +50 mV. The top trace is the time course of the experiment demonstrating that CO gradually increased BK channel activity defined by NPo to 322% (n=9) of the control value within 10 to 12 minutes. We also used CORM3 (100 µmol/L), a CO donor,18 to study the effect of CO on BK channels. Figure 3B is a whole-cell patch recording demonstrating that CORM3 mimicked the effect of CO and stimulated the BK channel activity. In contrast, the addition of solvent had no effect on channel activity (Figure 3C). Data summarized in Figure 3D and 3E show that application of CO and CORM3 increased the BK channel activity to 322% and 392% of the control value (n=9), respectively.
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After showing that application of exogenous CO activated BK channels in endothelial cells, we investigated whether stimulation of endogenous CO synthesis could also mimic the effect of CO or a CO donor on BK channels. We first examined whether heme oxygenase (HO)-1 and HO-2 are expressed in HUVECs. Figure 4A is a Western blot showing that both HO-1 and HO-2 are expressed in the endothelial cells in 4 experiments. We then used hemin, the substrate of HO,23 to examine whether stimulation of endogenous CO production was able to increase BK channel activity in HUVECs. Data summarized in Figure 4B demonstrate that application of 20 µmol/L of hemin significantly stimulated BK channels by 478% (n=5), and increasing hemin concentration to 40 µmol/L augmented the channel further to 4000% (n=7) of the control value. Figure 4C includes a typical channel activity showing that addition of 40 µmol/L of hemin stimulates the BK channel activity. To exclude the possibility that the stimulatory effect of hemin on the BK channel was because of factors other than CO, we examined the effect of hemin on BK channels in the presence of SnMP (20 µmol/L), an agent that inhibits HO activity. Inhibition of endogenous HO did not significantly affect the BK channel activity (n=5; Figure 5D), suggesting that endogenous CO was not involved in determining the basal level of BK channel activity under present experimental settings. However, SnMP completely abolished the effect of 20 µmol/L (Figure 4B) and significantly attenuated the stimulatory effect of 40 µmol/L of hemin on BK channels (Figure 4E). The observation that hemin produced a larger increase in channel activity than that with CO or CORM3 suggests a possibility that CO levels induced by application of hemin may be higher than that with CO-bubbled solution or CORM3, which reaches the BK channels through a slow diffusion. Thus, our data strongly suggest that CO stimulates BK channel activity and that the endogenous HO is involved in the regulation of BK channels.
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CO Stimulates BK Channels via Both NO-Dependent and NO-Independent Mechanisms
It has been reported that NO stimulates BK activity.12,24 Because CO has been shown to increase NO release,25 we examined whether the stimulatory effect of CO on BK channels was the result of enhancing NO release, which, in turn, activated BK channels. We first studied the effect of NO on BK channels in HUVECs using 2 NO donors, sodium nitroprusside (SNP) and diethylamine NONOate. After forming the whole-cell patch mode, the membrane potential was clamped at +50 mV, and channel activity was registered for 2 to 3 minutes before adding the NO donor. Figure 5A is a recording showing the effect of 50 µmol/L of SNP on the channel activity. Addition of SNP significantly increased NPo to 180% (n=6) of the control value. Moreover, the stimulatory effect of SNP was mimicked by diethylamine NONOate. Data summarized in Figure 5B demonstrate that 100 µmol/L of diethylamine NONOate significantly increased the BK activity to 336% of the control value (n=5) within 3 minutes.
We then examined the effect of CO on BK channels in endothelial cells pretreated with NG-nitro-L-arginine methyl ester (L-NAME) to block endogenous NO generation. Figure 6A is a recording demonstrating that CO still increased the BK channel activity in the presence of L-NAME (100 µmol/L). However, the onset of the stimulatory effect in endothelial cells pretreated with L-NAME was longer than those in cells pretreated with NG-nitro-D-arginine methyl ester hydrochloride (D-NAME). Data summarized in Figure 6B show that CO did not significantly increase the BK channel activity within first the 3 minutes. In contrast, CO stimulated BK channel activity within the same time range in the presence of D-NAME (n=5), an agent that does not block the NO formation. This suggests that the early stimulatory effect of CO was possibly mediated by NO. However, from inspection of Figure 6A, it is apparent that CO still stimulated BK channel activity in the presence of L-NAME and increased channel activity to 195% (n=7) of the control value within 12 minutes (Figure 6B). This suggests that CO is able to stimulate BK channel activity by an NO-independent mechanism.
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CO Stimulates BK Channel via Both Soluble Guanylate Cyclase-Dependent and -Independent Mechanisms
CO has been shown to stimulate soluble guanylate cyclase (sGC)26 and increase cGMP production, which is known to activate BK.12 Thus, we examined whether the stimulatory effect of CO on BK channels was the result of activation of sGC by examining the effect of CO on BK channels in the absence and presence of 1 µmol/L of 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), an inhibitor of sGC. We pretreated the endothelial cells with ODQ for 15 minutes and examined the effect of CO in the presence of ODQ. Although application of 1 µmol/L of ODQ had no significant effect on BK channels (data not shown), inhibition of sGC abolished the early (within 3 minutes) stimulatory effect of CO on BK channels (left panel of Figure 6C). This suggests that the early effect of CO on BK channels is possibly mediated by stimulation of sGC. However, inhibition of sGC did not affect the late (between 10 and 12 minutes) effect of CO, because it increased BK channel activity to 244% (n=7) of the control value (right panel of Figure 6C). Therefore, the late phase of the stimulatory effect of CO on BK channels appears to involve a sGC-independent mechanism. We have also examined the effect of CO on BK channels in the presence of KT5823 (1µmol/L), an inhibitor of protein kinase G. Data summarized in Figure 6C demonstrate that inhibiting protein kinase G abolished the early effect of CO on BK channels but did not abolish the late effect on BK channels. The notion that the early effect of CO on BK channels depends on protein kinase G was also suggested by observation that inhibition of PKA with 0.5 µmol/L of KT5720 had no effect on the CO-induced stimulation of BK channels in both early and late phases (Figure 6C). Moreover, application of the solvent had no effect on channel activity in the presence of either ODQ or KT5823 (data not shown). Thus, the present results indicate that the early effect of CO on BK channels is related to the NO-cGMP-protein kinase G pathway.
CO-Induced Stimulation of the BK Channel Is Independent From Ca2+ and Redox Signaling
Because the BK channels are gated by both voltage and Ca2+, we examined whether removal of Ca2+ from the pipette solution (intracellular solution) could abolish the stimulatory effect of CO on BK channels. Figure 7A summarizes results demonstrating the effect of CO on BK channels in endothelial cells, which were perfused with Ca2+-free pipette solution containing 10 mmol/L of EGTA, 10 µmol/L of ryanodine, and 1 mg/mL of heparin. In the absence of Ca2+, CO still increased channel activity to 192% (n=8) of the control value within 10 to 12 minutes. This suggests that the CO-induced stimulation of BK channels does not require the involvement of Ca2+.
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A previous study showed that CO interacts with redox signaling,27 and hydrogen peroxide has been shown to activate BK channels in human endothelial cells17 and in coronary smooth muscle cells.28 To determine whether CO stimulates BK channels via altering redox signaling, we examined the effect of CO in the presence of 10 µmol/L of ebselen, a scavenger of reactive oxygen species.29 We first studied the effect of 100 µmol/L of H2O2 on BK channels in the presence or absence of ebselen in the Ca2+-free pipette solution (intracellular solution). Data summarized in Figure 7B demonstrate that application of H2O2 increased BK channel activity to 215% (n=11) of the control value (Ca2+-free pipette solution) and that the stimulatory effect of H2O2 was significantly attenuated by ebselen (n=9). However, application of ebselen (Ca2+ -free pipette solution) did not prevent the stimulatory effect of CO on BK channel activity (211% of the control value; n=9; Figure 7C).
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Discussion |
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We confirmed previous reports from other investigators that BK channels are expressed in the endothelial cells.22,30,31 The role of BK channels in the regulation of endothelial function is still poorly understood. Because BK channel activity is low under control conditions, it is generally assumed that BK channel activity plays a minor role in determination of the membrane potential of endothelial cells under resting conditions when the intracellular Ca2+ is low. However, there is evidence suggesting that BK channels could be activated under some circumstances. For instance, depletion of cholesterol has been shown to activate BK channels in bovine aortic endothelial cells.30 The present study demonstrated that BK channel activity in cultured endothelial cells is stimulated by CO and NO. It has been reported that the K channel population in cultured endothelial cells may be different from those in the native cells.1 For instance, Kir has been shown to be highly expressed in the native endothelial cells but only a fraction of HUVECs express Kir. However, BK channels have been demonstrated to be expressed in the native endothelial cells and cultured endothelial cells.1 Thus, it is conceivable that BK channels participate in generating the membrane potential of endothelial cells in experimental settings in which the generation of NO and CO is enhanced.
Two lines of evidence indicate that CO stimulates the BK channels: application of either CORM3 or CO increased BK channel activity, and addition of hemin can also activate BK channels. The observation that inhibition of HO diminishes the stimulatory effect of hemin further suggests that endogenous CO is involved in the regulation of BK channels. Our present study has confirmed previous findings that both HO-1 and HO-2 are expressed in HUVECs.32 However, we could not determine whether HO-1 or HO-2 is mainly responsible for generating CO under present experimental conditions, because no specific inhibitor for either HO-1 or HO-2 is available. HO-2 is constitutively expressed, whereas HO-1 expression is inducible and increased in response to oxidative stress.33 It has been shown that hypoxia stimulates CO production in endothelial cells.34 HO converts heme to iron, biliverdin, and CO.33 Although biliverdin is a strong antioxidant that affects redox signaling, CO has been reported to affect a variety of heme-containing proteins, including protein kinases35 and K channels. It has been reported that CO activates BK activity in smooth muscle cells14,19,36,37 and apical renal outer medullary K channel-related K channels in the thick ascending limb of the rat kidney.38 Because BK channels are involved in generating the membrane potential in smooth muscle cells, CO-induced activation of BK channel is expected to hyperpolarize the membrane potential and to decrease Ca2+ influx in the smooth muscle. Indeed, it has been shown that CO caused vasodilation by activation of BK channels and suppression of voltage-dependent Ca2+ channel activity in the smooth muscle.14 This mechanism could play an important role in mediating CO-induced vasodilation in the rat-tail artery19 and rat gracilis muscle arterioles.13
There are several mechanisms by which CO activates BK channels: (1) CO could increase NO release, which, in turn, activates BK channels; (2) CO could increase the production of superoxide, alter redox signaling, and increase the production of superoxide anions; (3) CO stimulates sGC and increases cGMP formation in endothelial cells; and (4) CO activates BK channels by direct modification of BK channel protein.39 The observation that inhibition of NO synthesis abolished the early effect of CO on BK channel activity supports the notion that CO-induced activation of the BK channel is at least partially mediated by NO. Several studies have reported the similar finding that CO increases NO release in endothelial cells25 and smooth muscle cells.18,40 Because NO has been shown to stimulate endothelial BK,41 we speculate that CO could increase NO release from intracellular NO pools, which, in turn, stimulates BK channel activity in endothelial cells. Thus, when NO levels were depleted after the inhibition of NO synthesis, the stimulatory effect of CO was diminished. However, the finding that CO could still significantly stimulate BK channels in the presence of L-NAME suggests that CO can also activate BK channels by an NO-independent pathway.
CO has been shown to alter the generation of reactive oxygen species, which could activate BK channels. In bovine pulmonary artery endothelial cells, CO increases the generation of peroxynitrite.27 Because BK channels have been demonstrated to be activated by reactive oxygen species,42 such as hydrogen peroxide17,28 and peroxynitrite,41,43 it is possible that CO activates BK channels by changing the reactive oxygen species level in endothelial cells. However, this possibility is unlikely in view of our finding that application of an antioxidant did not prevent CO-induced stimulation of BK channels. In contrast, application of ebselen significantly diminished the stimulatory effect of hydrogen peroxide on the BK channel. Thus, it is unlikely that the CO effect on the BK channel is the result of modification of redox status in endothelial cells.
CO has been shown to mimic the effect of NO and directly activate sGC.26 Also, it has been reported that inhibition of sGC attenuated the stimulatory effect of CO on BK channels in smooth muscle cells.19 The finding that inhibition of sGC prevents the early effect of CO on BK channels suggests that the stimulatory effect of CO depends, at least in part, on the activation of sGC in endothelial cells. However, the observation that inhibition of sGC failed to abolish the stimulatory effect of CO on BK channels suggests that CO stimulates BK channels via a cGMP-independent mechanism. The fact that inhibition of sGC mimicked the effect of L-NAME and abolished the early effect of CO on BK channels indicates that the early stimulatory effect of CO may be the result of activation of an NO-sGC pathway.
Finally, it has been demonstrated that CO regulates BK channels by regulation of the interaction between CO and heme. BK channel activity has been shown to be inhibited by heme, which binds directly to histidine residue of the 
subunit of BK channels.39 CO is able to replace heme on histidine residue and accordingly releases the heme-induced inhibition of BK channels. It has also been reported that CO stimulates BK channels through CO binding to histidine residue of BK channel proteins in smooth muscle cells.44 Because the stimulatory effect of CO on BK channels is still observed in the presence of sGC and NO synthase inhibitors and antioxidants, we speculate that the effect of CO on BK channels may be partially induced by modulation of BK channel proteins. However, further experiments are required to examine the mechanism by which CO modulates BK channel activity by an NO-independent way. We conclude that BK channels are expressed in human endothelial cells and that CO activates the BK channels by a mechanism involving increased NO release and possible modulation of BK channel proteins.
Perspectives
The CO-induced activation of BK channels should play an important role in the regulation of vascular function. We speculate that CO activates BK channels in endothelial cells and hyperpolarizes the membrane potential. As a consequence of hyperpolarization, the driving force for Ca2+ influx increases, and raised intracellular Ca2+ concentration could stimulate NO generation, which diffuses into the smooth muscles cells to activate BK channels. In addition, it has been demonstrated that K effluxes via charybdotoxin-sensitive K channels are responsible for the relaxation of smooth muscle cells in rat arteries.45 Thus, CO-induced activation of BK channels increases K efflux and raises the K concentration between endothelial cell and smooth muscle cells. This increase in K concentrations leads to hyperpolarization of the adjacent smooth muscle cells. Thus, CO could be a candidate for the hyperpolarization factor.
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Acknowledgments |
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Sources of Funding
This work was supported by National Institutes of Health grants HL34100 (W.-H.W.). D.-L.D. was supported by Natural Science Foundation of China (30672461), and B.-F.Y. was supported by Natural Science Foundation of China (30430780).
Disclosures
None.
Received June 7, 2007; first decision June 22, 2007; accepted August 2, 2007.
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