Published online before print September 20, 2007, doi: 10.1161/CIRCRESAHA.107.159053
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© 2007 American Heart Association, Inc.
Integrative Physiology |
Role of Ca2+-Independent Phospholipase A2 and Store-Operated Pathway in Urocortin-Induced Vasodilatation of Rat Coronary Artery
From the Laboratorio de Investigación Cardiovascular (T.S., A.D.-R., E.C.-S., A.O.), Hospital Universitario Virgen del Roció, Universidad de Sevilla, and Centro Andaluz de Biología Molecular & Medicina Regenerativa (A.H., A.H.-L.), Sevilla, Spain.
Correspondence to Tarik Smani, PhD, Laboratorio de Investigación Cardiovascular, Quirófanos Experimentales, Hospital General Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, E-41013 Sevilla, Spain. E-mail tasmani{at}us.es
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Abstract |
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Urocortin has been shown to produce vasodilatation in several arteries, but the precise mechanism of its action is still poorly understood. Here we demonstrate the role of store operated Ca2+ entry (SOCE) regulated by Ca2+-independent phospholipase A2 (iPLA2) in phenylephrine hydrochloride (PE)-induced vasoconstriction, and we present the first evidence that urocortin induces relaxation by the modulation of SOCE and iPLA2 in rat coronary artery. Urocortin produces an endothelium independent relaxation, and its effect is concentration-dependent (IC50
4.5 nmol/L). We show in coronary smooth muscle cells (SMCs) that urocortin inhibits iPLA2 activation, a crucial step for SOC channel activation, and prevents Ca2+ influx evoked by the emptying of the stores via a cAMP and protein kinase A (PKA)–dependent mechanism. Lysophophatidylcholine and lysophosphatidylinositol, products of iPLA2, exactly mimic the effect of the depletion of the stores in presence of urocortin. Furthermore, we report that long treatment with urocortin downregulates iPLA2 mRNA and proteins expression in rat coronary smooth muscle cells. In summary, we propose a new mechanism of vasodilatation by urocortin which involves the regulation of iPLA2 and SOCE via the stimulation of a cAMP/PKA-dependent signal transduction cascade in rat coronary artery.
Key Words: urocortin • iPLA2 • vasoconstriction • store operated Ca2+ entry • cAMP-PKA
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Introduction |
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Coronary artery smooth muscle cells (SMCs) regulate vascular tone influencing perfusion of the heart, peripheral resistance, and as a consequence heart function. Agonist induces a contraction of vascular SMCs by a rise in cytosolic free Ca2+ concentration1,2 because of a rapid Ca2+ release by InsP3 from intracellular stores and a transmembrane Ca2+ influx through L-type voltage-dependent Ca2+ channels or nonvoltage-gated channels such as store-operated Ca2+ (SOC) channels. The relative contribution of each channel depends on the smooth muscle type.2–4 The use of selective inhibitors of sarcoplasmic reticulum Ca2+-ATPase pump, as thapsigargin (TG), to activate SOC channels not only increases Ca2+ influx but also enhances tone in a variety of SMCs.3,5 Recently we showed Ca2+-independent phospholipase A2 (iPLA2) to be a crucial determinant of store-operated Ca2+ entry (SOCE). We demonstrated that the emptying of the stores activated iPLA2 and its lysophospholipid products opened the SOC channels in aortic SMCs and nonexcitable cells.6–8 Thus iPLA2 became a potential physiological target for regulation and fine-tuning of SOCE by other signaling cascades in SMCs.
A few years ago a new 40-aa peptide, urocortin,9,10 related to corticotropin-releasing factor (CRF) was described as a new player in cardiac control,11,12 and was proposed to protect cardiac myocytes during ischemia/reperfusion by downregulating iPLA2 expression.13,14 Urocortin also emerged as a potent vasodilator peptide, and its mechanism of action appears to be complex, eg, vasodilatation has been reported to be both endothelium-dependent and independent in coronary artery15,16 and in other vessels.16–18 The vascular effects of urocortin are mediated by the CRF receptors 2 (CRF-R2) which predominate in blood vessels.12,20 Binding of urocortin to CRF-R2 increases its affinity for the Gs protein leading to the stimulation of cAMP/PKA pathway (for review see12). Furthermore, cAMP-dependent protein kinase seems to modulate SOC channels in rabbit portal vein and in airway smooth muscle.21,22
Because urocortin modulates iPLA2 activity and expression in cardiomyocytes, here we test whether urocortin could modulate iPLA2 and in consequence SOCE that might regulate vascular tone of coronary artery. We unveil new important data of the mechanism by which urocortin relaxes rat coronary artery that include cAMP increase, iPLA2 activity and expression modulation, and SOCE regulation in rat coronary SMCs.
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Materials and Methods |
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Expanded details of all the methods are given in the supplemental data (available online at http://circres.ahajournals.org).
Cells and Arteries Preparation
Isolated rat coronary arteries were dissected from the heart, and SMCs were dispersed acutely or primary cultured as detailed in the online supplemental data. Isometric tension of rat coronary rings was measured in an organ chamber as previously described.23
Measurement of Contractility in Arterial Rings
Rat coronary arteries were obtained from 2-month-old Wistar male rats. Arteries were cleaned of connective tissue, cut in rings (2 mm), and mounted on a small-vessel myograph (JP Trading) to measure isometric tension connected to a digital recorder (Myodataq-2.01, Myodata-2.02 Multi-Myograph System).
Intracellular Ca2+ and Mn2+ Measurement
Dual-excitation imaging with fura-2 was used to measure cytosolic Ca2+ and Mn2+ changes in isolated SMCs as previously shown.6–8
Molecular Studies
The activity of iPLA2 was performed as described.6–8 The Kinase-Glo Luminescent Kinase Assay (Promega) was used to measure the PKA activity in coronary arteries after the indications of the manufacturers. Q-PCR, Western blot, and immunostaining were used to determine iPLA2 expression in coronary SMCs.
Statistical Analysis
Group data are presented as mean±SEM. Single or paired Student t test was used to determine the statistical significance of the obtained data. The difference was considered significant at P<0.01 and is marked by * in the figure.
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Results |
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Urocortin Induces Dose-Dependent Relaxation of Rat Coronary Artery
The cumulative addition of urocortin to coronary artery precontracted with phenylephrine (PE) induced a concentration-dependent relaxation with an IC50
4.5 nmol/L, and maximum relaxation (84%) was observed with 10 nmol/L urocortin (Figure 1A). Pretreatment of the arteries with L-NNA (100 µmol/L) to inhibit nitric oxide synthase and endothelial-mediated relaxations induced a small and nonsignificant effect on urocortin dose-dependent relaxation (Figure 1A, right panel). Meanwhile, urocortin (10 to 100 nmol/L) failed to relax the contraction induced by high K+ that involve L-type Ca2+ channels pathway (Figure 1B). Furthermore, in presence of 500 nmol/L nifedipine (the selective inhibitor of L-type Ca2+ channels), PE was able to produce a small but noticeable contraction that was relaxed by urocortin (Figure 1C) suggesting that urocortin-induced relaxation may occur independently of L-type Ca2+ channels pathway.
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Contribution of SOCE and iPLA2 in PE-Induced Contraction
Agonist-induced contraction may involve nonvoltage-gated channels such as SOC channels; therefore the contribution of SOCE in coronary vascular tone was examined. Supplemental Figure Ia and Ib shows that PE-induced contraction was relaxed in a dose-dependent manner by 2 aminoethoxydiphenyl borate (2APB) and diethylstilbestrol (DES), inhibitors of SOC channels.24–27 Moreover and because we recently demonstrated that iPLA2 is involved in SOCE, we found that inhibition of iPLA2 by bromoenol lactone (BEL) relaxed gradually the artery (supplemental Figure Ic). Although BEL is a potent iPLA2 inhibitor, it also inhibits phosphatidate phosphohydrolase-1 (PAP-1).28,29 To block the activity of PAP-1, we pretreated the artery with 50 µmol/L propanolol (PAP-1 specific inhibitor) and observed that propanolol failed to prevent BEL-induced relaxation confirming that PAP-1 is not involved in BEL effect (data not shown). In addition, in isolated fresh and cultured coronary SMCs, 2APB (75 µmol/L), DES (1 µmol/L), and BEL (25 µmol/L) inhibited TG- (2 µmol/L) evoked Ca2+ and Mn2+ influx (supplemental Figure II), like the data in aorta SMCs.6,7,26 Importantly, when the contraction was induced by depolarization with high K+, 2APB and BEL failed to relax the arteries (supplemental Figure III).
Role of Store-Operated Ca2+ Entry in Urocortin-Induced Vasorelaxation
We then checked the role of SOC channels in urocortin effect on contraction. Figure 1D shows that the activation of SOCE with thapsigargin (TG, 10 µmol/L) caused a contraction that was 93% relaxed by urocortin (10 nmol/L). Interestingly as shown in Figure 1E, TG-induced contraction was also relaxed 69% by nifedipine (1 µmol/L) indicating a possible coactivation of SOC and L-type Ca2+ channels as reported in other SMCs.30 We further performed experiments in acutely dispersed and primary cultured rat coronary SMCs loaded with fura-2 to examine the effect of urocortin on TG-induced SOCE, and we observed that 10 minutes pretreatment with urocortin (10 nmol/L) prevented TG-induced Ca2+ entry in fresh (Figure 2B) and cultured (Figure 2C) SMCs. It is important to note that urocortin effect was specific to Ca2+ influx and did not alter TG-induced Ca2+ release from the stores. This observation was confirmed when low concentration of ionomycin (100 nmol/L) was used to release Ca2+ from the store as described.31 
ratio of ionomycin-induced Ca2+ release was 0.23±0.01 in control versus 0.22±0.02 in urocortin treated SMCs (n=3 cultures). Furthermore, to exclude the influence of mechanisms that remove Ca2+ from the cytoplasm, we used Mn2+-quench technique considered more direct measurement of ion channel mediated cation influx in intact cells.6,24,32 Indeed, TG-induced Mn2+ influx was also inhibited by urocortin in cultured (Figure 2D) and freshly isolated coronary SMCs (Figure 2E). All together suggest that urocortin modulates agonist-induced contraction of rat coronary artery apparently by SOCE regulation.
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Urocortin Modulates iPLA2 Activity and Expression in Coronary SMCs
Urocortin has been shown to protect the heart against ischemia-reperfusion by iPLA2 downregulation,13,14 thus we investigated whether urocortin could modulate iPLA2 activity and expression in coronary artery. First, the activation of iPLA2 by the depletion of Ca2+ stores was determined in coronary SMCs, and consistent with previous reports,6–8,33 TG enhanced iPLA2 activity in control coronary SMCs whereas in SMCs treated with urocortin (100 nmol/L) for 10 minutes the iPLA2 activity was decreased about 80% (Figure 3A). In addition, the expression of iPLA2 was assessed using real-time quantitative PCR. We observed a concentration-dependent decrease of iPLA2 mRNA in SMCs treated 24 hours with urocortin and 100 nmol/L urocortin decreased 58% of iPLA2 mRNA expression (Figure 3B). In addition Western blot study showed that 100 nmol/L urocortin also downregulated about 45% of iPLA2 protein expression (Figure 3C). These results determine that urocortin can modulate iPLA2 activity and expression in coronary SMCs that may be crucial for SOCE regulation.
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The activation of iPLA2 releases lysophospholipids and arachidonic acid7,28 that can be metabolized by cyclooxygenase (COX).34 To asses the role of COX pathway in urocortin response, PE was administrated in presence of indomethacin, a widely used COX inhibitor; and consistent with previous data in aorta,35 PE in presence of 10 µmol/L indomethacin induced a contraction of the same magnitude as in control (Figure 3D) which was relaxed by urocortin. These results discarded the involvement of COX regulation in urocortin-induced relaxation of coronary artery as it was shown previously.15
Urocortin Does Not Prevent SOCE Induced by iPLA2 Products, Lysophosphatidylcholine, and Lysophosphatidylinositol
Lysophospholipids has been shown to activate ionic channels in a membrane-delimited fashion.7,36 Here, we checked whether lysophospholipids could mimic the effect of the depletion of the stores as we showed previously in aortic SMCs and rat basophilic leukemia (RBL) cells,7 independently of urocortin’s negative modulation of iPLA2. In coronary SMCs treated with urocortin, lysophosphatidylcholine (LPC, 300 nmol/L) and lysophosphatidylinositol (LPI, 300 nmol/L) evoked practically the same Ca2+ (Figure 4A,C) and Mn2+ (Figure 4B and 4D) influx as in untreated SMCs, which were inhibited by 2APB consistent with the involvement of the SOC channels. These results suggest that urocortin is not inhibiting directly SOC channels and confirm that its effect is through iPLA2.
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Urocortin Inhibits SOCE and Contraction via a cAMP and PKA Signaling Pathway
We examined the effect of astressin, specific antagonist of CRF-R2, on contraction and SOCE. We observed that the application of astressin (500 nmol/L) blocked urocortin induced vasodilatation of coronary arteries (n=6, data not shown), and prevented the inhibition of TG-induced Ca2+ and Mn2+ influx by urocortin in SMCs as shown in Figure 2B, 2C, 2D, and 2E. CRF-R2 is functionally linked to the Gs protein that activates adenylate cyclase and cAMP production. We tested the effect of dibutyril-cAMP (db-cAMP, a cell permeable analogue of cAMP) on contraction and on TG-induced Ca2+ and Mn2+ influx. We found that db-cAMP (300 to 500 µmol/L) mimicked the effect of urocortin and induced a vasodilatation of PE- and TG-induced contraction (Figure 5A and 5B), whereas in fura-2 loaded fresh and primary cultured SMCs, db-cAMP (300 to 500 µmol/L) inhibited TG-induced Ca2+ (Figure 5C and 5D) and Mn2+ (Figure 5E and 5F) influx, similar to that observed with urocortin. Importantly, db-cAMP inhibited iPLA2 activity in the same way as urocortin (Figure 6B).
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Protein kinase A (PKA) is the major target of cAMP signaling and is known to contribute to its impact on vascular function.37 Therefore, we investigated whether PKA is involved in urocortin action on coronary vasorelaxation and on SOCE. Figure 6A shows that urocortin (100 nmol/L) increased PKA activity equally in coronary artery stimulated or not with PE (1 mmol/L). Conversely the inhibition of PKA with KT5720 (1 µmol/L) blocked urocortin-stimulated PKA activity (Figure 6A), and importantly it inhibited iPLA2 activation (Figure 6B). Additionally, PKA blocking prevented urocortin-induced relaxation of PE-induced contraction (Figure 6C) and its inhibition of the store-operated Ca2+ (Figure 5C and 5D) and Mn2+ influx (Figure 5E and 5F). Similar data were observed when H-89 (1 µmol/L) was used to inhibit PKA (data not shown). Importantly, the downregulation of iPLA2 protein expression (Figure 7A) by urocortin was reversed in SMCs pretreated previously with KT5720 (1 µmol/L). The immunostaining approach (Figure 7B) shows the faint fluorescence in urocortin-treated cells and the difference observed in the merged images. These results suggest that urocortin regulates iPLA2 activity and expression via a cAMP/PKA dependent mechanism which modulates SOCE in coronary artery.
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All together, our data suggest a new mechanism of urocortin effect on Ca2+ signaling and vascular tone that involves iPLA2 and the SOC pathway summarized in Figure 8. In this scenario, we suggest that an agonist that releases Ca2+ from intracellular stores activates iPLA2 and SOCE, which produces a vasoconstriction. We propose that the binding of urocortin to its receptor CRF-R2 stimulates the cAMP/PKA signaling pathway which we showed can negatively modulates iPLA2, "shut down" the store-operated pathway, and in consequence induces the vasorelaxation of coronary artery.
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Discussion |
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The major findings of this study describe a new mechanism for urocortin regulation of vascular tone that involves for the first time Ca2+-independent phospholipase A2 and SOCE modulation. We have shown that urocortin induced an endothelium-independent relaxation in contrast with the data showed previously where the potency of urocortin was proposed to decrease in the endothelium denuded coronary rings.15 The role of endothelium in urocortin effect varied depending on the arteries and apparently on the type of the contraction stimuli.15–19 Moreover diverse concentrations of urocortin were used to relax different vessels, which generally were higher than the physiological range described in human plasma membrane.38 In fact, a full relaxation was induced by 10 nmol/L urocortin in basilar artery18; 10 to 30 nmol/L of urocortin induced maximum relaxation in U46619 precontracted rat coronary and human mammary artery,15–17 100 nmol/L produced 60% relaxation of tail artery precontracted with high K+,19 meanwhile up to 206 nmol/L of urocortin caused a moderate decrease of coronary perfusion pressure in isolated rat heart.39 Here we showed that urocortin induced a potent relaxation with an IC50
4.5 nmol/L which is within the range of the relaxation described previously in coronary artery.15,16 Furthermore, we presented evidences that urocortin relaxed PE- and TG-activated coronary vasoconstriction by SOCE modulation. Importantly, TG-induced contraction seems to involve SMC depolarization and the consequent coactivation of SOC and L-type Ca2+ channel as it was reported previously in other SMCs.3,30 On the other hand, urocortin inhibited TG-induced store operated Ca2+ and Mn2+ influx that we recorded in fresh and primary culture of coronary SMCs. In fact, we confirmed that SOCE is involved in coronary vascular tone regulation. Unfortunately, the progress in the SOCE field has been severely hindered by the absence of relatively specific inhibitors of SOC channels; and despite the lack of specificity of 2APB it remains the most reliable and widely used inhibitor of SOCE.24,25 Diethylstilbestrol (DES) which has been demonstrated as more specific inhibitor for SOC channels in SMCs, RBL, and Platelets,26,27 inhibited SOCE in coronary SMCs and induced a very potent relaxation of coronary artery with an IC50 around 260 nmol/L, a very low concentration compared with 30 µmol/L that was proposed to inhibit L-type Ca2+ channels in A7r5 cells line.40 These results supported 2APB effects in coronary artery and ensured that we are targeting SOC pathway.
As reported iPLA2 activation is absolutely required for the activation of SOC channels and SOCE after depletion of Ca2+ stores.6–8,33 Here, we brought new and important data concerning the contribution of iPLA2 and SOCE on coronary vascular tone. Interestingly, urocortin inhibited the activity of iPLA2 in the same way as iPLA2 antisense and BEL as described.6,8,33 This inhibition suggests that the decrease of iPLA2 products will shut down the Ca2+ influx through SOC channels. Importantly in presence of urocortin LPC and LPI, iPLA2 products, evoked exactly the same 2APB sensitive SOCE as in control SMCs demonstrating that even when functional activity of iPLA2 is inhibited with urocortin its downstream products are capable of activating SOCE in SMCs. The ability of lysophospholipids to activate SOCE in the presence of urocortin ruled out any possibility that urocortin could be inhibiting SOC channels directly. Lysophospholipid activation of SOCE was originally proposed in SMCs and RBL cells7 and now are shown to activate SOC channels in rat cerebellar astrocytes34 and some TRP channels in prostate and in Human saphenous vein SMCs.35,41
Furthermore, we established that urocortin via the activation CRF-R2, stimulated cAMP/PKA pathway.11,12,20 Therefore we showed that db-cAMP mimicked the effects of urocortin and inhibited iPLA2 activity and SOCE as well as it relaxed TG- and PE-induced vasoconstriction; meanwhile we determined that urocortin regulation of iPLA2 activity, SOCE, and contractions are mediated by PKA. The precise mechanism(s) by which urocortin modulates iPLA2 through PKA remains to be determined, but it is known that iPLA2 possesses numerous potential sites for phosphorylation and its modulation by protein kinase has been proposed in coronary endothelial cells.42
Our interests in demonstrating that urocortin could modulate iPLA2 take us to a very intriguing outcome. Indeed, besides its acute effect on iPLA2 activation we found that urocortin downregulated iPLA2 expression. Real-time quantitative PCR, Western blot, and immunohistochemistry results showed that urocortin modulated iPLA2 expressions in coronary SMCs similar to that described in cardiomyocytes.13 Here, we gave new data and proof demonstrating that these effects can be observed also in SMCs and are dependent on a mechanism involving cAMP and PKA. The downregulation of iPLA2 by urocortin can be of major interest, as iPLA2 is known to participate in several important cell processes such as ischemia/reperfusion syndrome, cellular remodeling, and cell cycle progression.13,14,43,44
In summary, our results add further confirmations of the crucial role of the store-operated pathway and iPLA2 in the regulation of vascular tone and establish iPLA2 as a potential target for different signaling cascade as the one that involves urocortin, cAMP, and PKA. Independent lines of evidence presented here reveal urocortin, via a cAMP/PKA mechanism, as a negative modulator of iPLA2 activity which leads to the shut down of SOC channels, the inhibition of Ca2+ influx that provokes a vasodilatation of rat coronary artery as summarized in Figure 8. We believe that this novel finding may provide a new molecular basis for developing new therapeutic agents for cardiovascular diseases associated with iPLA2 modulation and Ca2+ regulation of vasoconstriction.
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Acknowledgments |
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We wish to thank Dr P. Perez for the valuable help and comments on the manuscript.
Sources of Funding
T. Smani is awarded by "Ramon y Cajal" fellowship. This study was supported by grants: Redes RECAVA, Fondos de Investigación Sanitaria (FIS, PI050396 and PI052106), Junta de Andalucía (182/2005,174/2006, P06-CTS-01711), and Fundación de Progreso y Salud.
Disclosures
None.
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Footnotes |
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Original received April 18, 2007; resubmission received July 3, 2007; revised resubmission received August 31, 2007; accepted September 12, 2007.
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