Published online before print February 23, 2006, doi: 10.1161/01.ATV.0000215179.76144.39
© 2006 American Heart Association, Inc.
Vascular Biology |
Competitive Binding of CREB and ATF2 to cAMP/ATF Responsive Element Regulates eNOS Gene Expression in Endothelial Cells
From the Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Japan.
Correspondence to Masahiko Kurabayashi, MD, PhD, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511, Japan. E-mail mkuraba{at}med.gunma-u.ac.jp
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Abstract |
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Objective— Expression of endothelial nitric oxide synthase (eNOS) is a critical determinant for vascular homeostasis. We examined the effects of Beraprost sodium (BPS), a stable analogue of prostacyclin, on the eNOS gene expression in the presence of inflammatory cytokine interleukin (IL)-1ß in cultured endothelial cells.
Method and Results— Exposure of human and bovine endothelial cells to IL-1ß decreased eNOS expression. Western blot analysis using phospho-specific antibodies showed that IL-1ß stimulated p38 MAP kinase and phosphorylated ATF2. BPS inhibited these effects via protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) activation. Transfection assays using site-specific mutation constructs showed that CRE/ATF elements located at –733 and –603 within the human eNOS promoter are necessary for full IL-1ß responsiveness. BPS attenuated the IL-1ß–mediated decrease in eNOS promoter activity and the expression of eNOS gene through PKA pathway. Electrophoretic gel mobility shift assays showed that IL-1ß increased the binding of phosphorylated ATF2 to CRE/ATF. On treatment with BPS, phosphorylated CREB predominantly bound to CRE/ATF.
Conclusions— These results indicate that IL-1ß and BPS antagonistically regulates the eNOS expression through the activation of p38 and PKA, respectively. Furthermore, the ability to bind both CREB and ATF2 implicates the CRE/ATF sequence as a potential target for multiple signaling pathways in the regulation of the eNOS gene transcription.
The expression level of the eNOS gene is a critical determinant of endothelial integrity. Beraprost sodium (BPS) inhibited the downregulation of eNOS gene expression by IL-1ß through competitive binding of ATF2 and CREB to ATF/CREB sequences. The data indicate a potential role of ATF/CREB family of transcription factors in atherosclerosis.
Key Words: cAMP • cytokine • endothelium • prostacyclin • transcription factor
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Introduction |
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Atheroprotective effects of endothelium are exerted through the biosynthesis and release of a variety of molecules such as nitric oxide (NO), prostacyclin (PGI2), tissue-type plasminogen activator and thrombomodulin (TM). A decrease in expression of endothelial NO synthase (eNOS), PGI2, tissue-type plasminogen activator, and TM is closely associated with cardiovascular events, including myocardial infarction, vasospasm, and stroke.1,2 Among these, a reduction of bioavailability of NO is a major determinant of endothelial dysfunction.3
Proinflammatory cytokines including IL-1ß play a key rule in endothelial dysfunction and development of atherosclerosis.4 Earlier studies showed that tumor necrosis factor (TNF)-
, hypoxia, or a high concentration of native low-density lipoprotein (LDL) decrease the eNOS expression by shortening eNOS mRNA half-life.5,6 Additional studies disclosed that the expression of eNOS gene is also regulated at the transcriptional levels. DNA sequence elements involving endothelial cell-specific expression of the human eNOS gene are localized to putative GATA and Sp1 binding sequence.7 Anderson et al showed that TNF- inhibits the eNOS gene promoter activity through NF-kB-mediated Sp1/Sp3 binding activity in bovine aortic endothelial cells.8 Neumann et al showed that TNF-–mediated eNOS transcription is regulated by GATA-4/Sp3 binding sites.9
In our previous study, we identified and characterized sequence elements homologous to the cAMP-responsive elements (CRE) at –733 and –603 within the human eNOS promoter, to which we refer CRE1 and CRE2, respectively. Although consensus CRE contain the conserved palindromic sequence TGACGTCA, CRE1 is TGCGTCA and CRE2 is AATGTCA, both of which contain only half site of CRE.10 Despite the apparently weak homology, we found that the CRE1 and CRE2 play an important role for the inducible expression of the human eNOS gene in response to Beraprost sodium (BPS) in bovine aortic endothelial cells.10 BPS is a stable prostacyclin analogue, and it mimics the biological properties of PGI2, such as an activation of adenylate cyclase and an increasing intracellular cAMP level through the activation of PGI2 receptor.11 BPS is now widely used for the treatment of the patients with primary pulmonary hypertension12 and atherosclerosis obliterans.13
Several factors that specifically recognize the CRE have been identified as members of the bZIP family, including CREB, CREM, ATF1, ATF2, and c-Jun.14 These transcription factors form both homodimeric and heterodimeric complexes. CREB:CREB, CREB:CREM,CREB:ATF1, and ATF2:c-Jun dimmers are all known to bind to palindromic CREs. The precise roles for each of these proteins in the activation and/or regulation of the eNOS gene are not known, but the ability to bind many members of the CREB/ATF family implicates the CRE as a potential target for multiple signaling pathways in the regulation of this gene.
Studies on the inducible expression in the cellular stress response including genotoxic agents, inflammatory cytokines, and ultraviolet (UV) irradiation have led to identification of ATF2 as an important transcription factor regulating cell growth, inflammation, and immune response. ATF2 target genes include TNF-,15 transforming growth factor-ß,16 cyclin A,17 E-selectin,18 and c-jun.19 ATF2 is characterized by its role in c-Jun NH2-terminal kinase (JNK)20 and p38 mitogen activated protein (MAP) kinase signal transduction pathways.21 Although ATF2 recognizes and binds specific ATF/CRE motifs as a homo- or heterodimer in the same fashion as CREB, the differential role of ATF2 and CREB remains largely uncharacterized.
In the present study, we tested the hypothesis that BPS prevents IL-1ß–mediated decrease in eNOS gene expression in endothelial cells. By analyzing the proteins binding to CRE/ATF within the human eNOS promoter, we provide evidence indicating that CREB and ATF2 antagonistically regulate eNOS transcription by competitively bind to CRE/ATF.
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Materials and Methods |
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The Material and Methods section can be found in an online supplement available at http://atvb.ahajournals.org.
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Results |
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IL-1ß Decrease eNOS mRNA and Protein Levels in Human Aortic Endothelial Cells and Bovine Aortic Endothelial Cells
To determine whether IL-1ß directly regulates eNOS expression, cultured human aortic endothelial cells (HAECs) were exposed to IL-1ß (10 ng/mL) for 24 hours. Results showed that IL-1ß evidently reduced eNOS mRNA and protein levels. This decrease was significantly attenuated in the presence of BPS (10 µmol/L) (Figure IA, IB, available online at http://atvb.ahajournals.org).
Furthermore, we examined the eNOS mRNA expression in bovine aortic endothelial cells (BAECs) exposed to various concentrations of IL-1ß (from 0 to 20 ng/mL) for 24 hours. IL-1ß significantly decreased eNOS mRNA levels (Figure 1A). Exposure of BAECs to various concentrations of BPS for 24 hours significantly inhibited the IL-1ß-mediated decrease in eNOS mRNA levels in a dose-dependent manner (Figure 1B). BPS also significantly blunted the IL-1ß-mediated the increase in plasminogen activator inhibitor (PAI)-1 and inducible NO synthase (iNOS) mRNA levels (Figure 1B). Consistent with the results of Northern blot analysis, IL-1ß reduced the levels of eNOS protein in a dose-dependent manner (Figure IIA, available online at http://atvb.ahajournals.org), and BPS attenuated this decrease (Figure IIB).
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IL-1ß Reduces eNOS Promoter Activity
To examine whether the decrease in eNOS mRNA levels by IL-1ß is regulated at the transcriptional levels, we performed the transient transfection assays of human eNOS promoter. Luciferase activity driven by the sequence containing 1.6 kbp of 5'-flanking region of the eNOS gene, to which we refer as –1600eNOS-Luc, was decreased by IL-1ß in a dose-dependent manner (Figure 2A). BPS attenuated such an effect of IL-1ß on the eNOS promoter activity (Figure 2B). Using several overlapping clones for 5'-flanking region of the eNOS promoter, we mapped IL-1ß–responsive sequence downstream of the –743 relative to the transcription start site (Figure 2C). We demonstrated that BPS activated the transcription of the human eNOS gene and CREs exist at –733 and –603, to which we refer CRE1 and CRE2, respectively.
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eNOS Gene Promoter Activity Is Decreased by ATF2
To determine whether ATF2 was involved in IL-1ß–mediated transcriptional repression of the eNOS gene in BAECs, we tested the effects of ATF2 overexpression on the –1600eNOS-Luc activity. Transient transfection of the expression vector for either ATF2 or CREB increased ATF2 or CREB protein levels by 2-fold (Figure III, available online at http://atvb.ahajournals.org). Cotransfection of –1600eNOS-Luc with ATF2 expression vector significantly decreased the luciferase activity. Conversely, overexpression of CREB significantly increased the luciferase activity of –1600eNOS-Luc. ATF1, c-Jun, and p65 had no measurable effects on –1600eNOS-Luc activity (Figure 3A). Furthermore, BPS overcome the reduction of eNOS promoter activity by ATF2 overexpression (Figure 3B).
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CRE Mediates IL-1ß Inhibition of eNOS Promoter Activity
To define the role of CRE within the eNOS promoter, we introduced substitution mutation into CRE1 and CRE2 sequence, and resultant plasmids were used for the transient transfection assays. The construct containing mutation in CRE1 in the context of –743eNOS-Luc, we designated it as –743(mCRE1)eNOS-Luc, showed lower luciferase activity as compared with wild-type construct –743eNOS-Luc (Figure 4). More importantly, IL-1ß–mediated reduction of luciferase activity was markedly attenuated in –743(mCRE1)eNOS-Luc. The construct, –613(mCRE2)-Luc, which contains mutation of CRE2 in the context of –613eNOS-Luc, was unresponsive to IL-1ß (Figure 4). Likewise, reduction of eNOS promoter activity by overexpression of ATF2 was markedly attenuated in –743(mCRE1)eNOS-Luc or –613(mCRE2)-Luc (Figure IV, available online at http://atvb.ahajournals.org). These results suggest that both CRE1 and CRE2 are involved in the downregulation of eNOS promoter activity by IL-1ß and ATF2.
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p38 MAP Kinase Mediates IL-1ß Inhibition of eNOS Expression
We used various protein kinase inhibitors to examine the intracellular signal transduction pathway that mediates the effects of IL-1ß on eNOS mRNA levels and luciferase activity of –1600eNOS-Luc in BAECs (Figure VA and VB, available online at http://atvb.ahajournals.org). IL-1ß–mediated MAP kinase pathways are principally observed in endothelial cells. At first, we examined the effects of MAP kinase inhibitors. The p38 MAPK inhibitor, SB203580 significantly attenuated the IL-1ß–mediated decrease in eNOS mRNA levels and eNOS promoter activity. In contrast, MEK-1 inhibitor (PD98059) had no measurable effects. In studies of other signal pathways, KT5720 (the PKA inhibitor), wortmannin (PI-3K inhibitor), protein phosphatase-1 (tyrosine kinase inactivator), tyrophostin A23 (Tyrosine kinase inhibitor), calphostin C (PKC inhibitor) also did not indicate measurable effects (Figure VA and VB). These results show that IL-1ß decreases eNOS gene expression through an activation of p38.
p38 and ATF2 Are Phosphorylated in Response to IL-1ß
To determine the effects of IL-1ß on p38, we performed Western blot analysis using antibody recognizing phosphorylated form of p38. The phosphorylation of p38 was detected by 0.5 hour after IL-1ß stimulation, peaked at 1 hour and the gradually declined thereafter (Figure 5A). This phosphorylation was inhibited by SB203580 (p38 inhibitor). Neither PD98059 (MEK-1 inhibitor) nor KT5720 (PKA inhibitor) inhibited the phosphorylation (Figure 5A).
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We next examined the phosphorylation of ATF2 by IL-1ß. Exposure of BAECs to IL-1ß induced phosphorylation of ATF2 at Thr69/71 (Figure 5B). The phosphorylation of ATF2 in response to IL-1ß was mediated by p38 because SB203580 completely blocked the effects of IL-1ß but not KT5720 (PKA inhibitors) and PD98059 (Figure 5B). It is noteworthy that BPS inhibited the phosphorylation of p38 and ATF2 in response to IL-1ß. This effect appeared to be mediated through the activation of PKA because PKA inhibitor KT5720 abrogated the effects of BPS on IL-1ß induction of phosphorylation of p38 and ATF2 (Figure 5A, 5B). These results suggested that IL-1ß induces ATF2 activation through the phosphorylation of p38, and BPS exerts its inhibitory effects on IL-1ß–mediated decrease in eNOS gene expression through the inhibition of IL-1ß–mediated phosphorylation of p38.
Binding of Phosphorylated ATF2 Is Increased in IL-1ß–Treated BAECs, and It Was Replaced by Phosphorylated-CREB in Response to BPS
To determine the nuclear factors that bind to CRE1 (TGCGTCA), we performed EMSAs by using the nuclear extracts from the BAECs and labeled probes containing CRE1 sequence. Incubation of the nuclear protein with the probe gave rise to prominent DNA: protein complex, C1. Both complexes were proved to be sequence-specific because the formation of C1 was inhibited by the molar excess amount of unlabeled wild-type oligonucleotides but not by the oligonucleotides containing mutations within CRE1 sequence, mCRE1 (Figure 6A).
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Supershift assay using anti-CREB antibody showed that both C1 complexes contain CREB, and the binding of CREB to CRE1 was significantly decreased in IL-1b–treated BAEC. Conversely, supershift assays using anti-ATF2 antibody revealed that complexes C1 contain more ATF2 rather than CREB in IL-1ß–treated BAEC. Interestingly, phospho-ATF2–specific antibody shifted the complexes (Figure 6B). As shown in Figure 6C, the binding of CREB, particularly phosphorylated CREB, to the CRE1 site was significantly increased in BPS+ IL-1ß–treated cells. On the contrary, the binding of ATF2 including its phosphorylated form was decreased in BPS+ IL-1ß–treated (Figure 6C). We repeated the same experiments to examine the nuclear binding to CRE2 (CRE2: AATGTCA) and obtained essentially the same results as the CRE1 probe (online data). These results suggest that phosphorylation of ATF2 by IL-1ß and phosphorylation of CREB by BPS are associated with the increase in DNA binding, and these 2 proteins competitively bind to CRE.
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Discussion |
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This study examined the molecular mechanisms and signaling pathways mediating BPS regulation of eNOS gene expression in IL-1ß–stimulated endothelial cells. Our studies suggest that BPS inhibits the IL-1ß-mediated decrease in eNOS gene transcription by inducing CREB phosphorylation and concomitantly by inhibiting ATF2 phosphorylation, which in turn increases the binding of CREB and decreases the binding of ATF2 to CRE. Thus, our data imply that CREs of the eNOS promoter play a positive or negative regulatory role, and eNOS gene expression is reciprocally regulated through PKA/CREB and p38MAPK kinase/ATF2 pathways.
BPS and IL-1ß Alter the Composition of the Proteins Binding to the eNOS CRE
Three families of leucine zipper proteins, CREB, ATF, and c-Fos/c-Jun, have been shown to activate or inhibit gene expression by binding to CRE/ATF sites as homo- or heterodimers.22,23 Composition of the proteins binding to CRE/ATF site is known to be different depending on the CRE sequence and the cell types.24 Although palindromic CRE bind strongly to several members of the bZIP family, including CREB, ATF1, ATF2, and c-Jun, variant CRE binds to predominantly ATF2 and c-Jun. Our EMSA using BAEC nuclear extracts showed that the variant CRE of eNOS promoter can bind both ATF2 and CREB. Although we did not compare the binding affinity of eNOS CRE/ATF sequence between CREB and ATF2, it is likely that ATF2 is more vigorously bind CRE than CREB. Clear detection of the binding of CREB to the variant CRE is probably because CREB is abundant species in our nuclear extracts.
Our EMSA showed that IL-1ß increased the binding of ATF2, whereas ATF2 protein levels were not altered as determined by Western blot analysis. Furthermore, BPS reduced the binding of ATF2 without affecting ATF2 protein expression (Figure 6; Figure VI, available online at http://atvb.ahajournals.org). These results indicate that DNA-binding activity of ATF2 is affected by its phosphorylation state. Consistently, the previous report described that the basic leucine zipper DNA-binding domain of ATF2 is engaged in an activation domain by intramolecular interaction, and inducers such as inflammatory cytokines disrupt this interaction to activate transcription and DNA binding.25
ATF2 Represses the eNOS Gene Transcription
Although increasing number of studies indicate that proinflammatory agents, including IL-1ß and TNF-, activate the p38 pathways, the involvement of p38 in endothelial cells has been somewhat controversial because some studies using SB203580 have found no involvement of p38 in IL-1ß-induced IL-8 production in human umbilical vein endothelial cells, whereas other studies using the same inhibitor have shown the significant effects on IL-1ß and TNF-–induced IL-8 and MCP-1 production by respiratory and umbilical endothelial cells.26–28 The p38 MAP kinase pathway also phosphorylates eNOS protein and increases NO production in endothelial cells.29 Thus, we examined the mechanisms of p38MAPK-mediated eNOS gene regulation and confirmed the IL-1ß-induced p38 phosphorylation by using the antibody that specifically reacts with phosphorylated form of p38 at Thr180 (Tyr182). In agreement with the previous studies, our data show that IL-1ß phosphorylates ATF2 and this is inhibited by SB203580. Because SB203580 acts as a selective inhibitor of p38 and p38ß at the concentration used in this study, we conclude that p38 mediates IL-1ß–induced ATF2 phosphorylation.
Phosphorylation of ATF2 at Thr69, Thr71, Thr73, which lie close to the NH2-terminal transcriptional activation domain, stimulates its transcriptional capacity.30 In this study, however, we show that phosphorylated ATF2 appears to repress the eNOS promoter activity. Although we have not explored mechanisms underlying this observation, it seems possible that this silencing effect on eNOS transcription cold be attributed to squelching of a positive factor as a result of efficient heterodimerization between ATF2 and other bZIP family members. Sequestration of cofactors such as p300 could also bring about negative transcriptional regulation. Further studies are obviously required to test these hypotheses.
Do CREB and ATF2 Antagonistically Regulate the Expression of Other Endothelial Genes?
Many classic cAMP-mediated vasodilators (including isoproterenol, PGI2, adrenomedullin, and adenosine) exert their vasorelaxant effects via receptor-mediated activation of adenylate cyclase, formation of cAMP and activation of PKA. In addition, activation of cAMP/PKA pathway has been implicated in the protection of endothelial cells against cellular stress. For example, the induction by lipopolysaccharide and TNF- of cell adhesion molecules such as vascular cell adhesion molecule-1, endothelial leukocyte adhesion molecule-1 (ELAM-1, or E-selectin), intercellular adhesion molecule-1, and tissue factor is reduced by drugs that elevate cAMP.31 Qiao et al indicate that cAMP-PKA pathway indicates a protective mechanism against endothelial barrier dysfunction via inhibition of RhoA activation.32 Moreover, a decrease in intracellular cAMP levels by hypoxia reduces endothelial NO production and thus induces endothelial cell damage.33 Therefore, our data seem to be relevant to the beneficial effects of BPS in BERCI-II trial in which BPS reduced the cardiovascular event rate in patients with ASO during 4-year of follow-up.13
In conclusion, we show for the first time to our knowledge that IL-1ß inhibition of the eNOS gene expression is regulated at least partly at the transcriptional levels in vascular endothelial cells, and that BPS attenuated these changes. Antagonistic regulation of CRE/ATF-containing eNOS promoter by IL-1ß and BPS is executed by the interaction between BPS-induced cAMP/PKA/CREB pathway and IL-1ß-induced p38/ATF2 pathway. It is particularly noteworthy that BPS and IL-1ß alter the composition of nuclear proteins that bind to eNOS CRE/ATF sequence.
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Acknowledgments |
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This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sport, and Culture of Japan and a grant from the Japan Cardiovascular Foundation.
Received September 11, 2005; accepted February 8, 2006.
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