Published online before print April 2, 2007, doi: 10.1161/HYPERTENSIONAHA.106.082479
(Hypertension. 2007;49:1378.)
© 2007 American Heart Association, Inc.
Original Articles |
Regulation of Scavenger Receptor Class BI Gene Expression by Angiotensin II in Vascular Endothelial Cells
From the Division of Endocrinology and Metabolism, Department of Internal Medicine (X.Y., K.Murao, H.I., W.-M.C., J.L., K.Matsumoto, T.N., R.A.M.A., T.I.), and Department of Cardiovascular Physiology (H.K.), Faculty of Medicine, Kagawa University, Kagawa, Japan; the Departments of Medicine and Biochemistry and Molecular Biology (N.C.W.W.), Faculty of Medicine, University of Calgary, Health Sciences Center, Calgary, Alberta, Canada; and the Departments of Medicine and Physiology and Biophysics (T.G.U.), University of Illinois at Chicago College of Medicine and Jesse Brown VA Medical Center.
Correspondence to Koji Murao, Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki-cho, Kita-gun, Kagawa 761-0793, Japan. E-mail mkoji{at}kms.ac.jp
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Abstract |
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High-density lipoprotein mediates a normal physiological process called reverse cholesterol transport. In this process, a scavenger receptor of the B class (SR-BI)/human homologue of SR-BI, CD36, and LIMPII analogous-1 (hSR-BI/CLA-1) facilitates the cellular uptake of cholesterol from high-density lipoprotein. In endothelial cells, high-density lipoprotein activates endothelial NO synthase via hSR-BI/CLA-1. Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis and modulates the expression of endothelial NO synthase. In the present study, we have examined the role of Ang II on hSR-BI/CLA-1 expression in human umbilical vein endothelial cells. Our results showed that endogenous expression of hSR-BI/CLA-1 was suppressed by exposure to Ang II in human umbilical vein endothelial cells. Administration of the Ang II type-1 receptor blocker olmesartan inhibited Ang II–induced hSR-BI/CLA-1 protein repression. In Ang II–treated cells, high-density lipoprotein had no effect on endothelial NO synthase activation. Ang II decreased transcriptional activity of the hSR-BI/CLA-1 promoter. The inhibitory effect of Ang II on hSR-BI/CLA-1 promoter activity was abrogated by wortmannin and LY294002, specific inhibitors of phosphatidylinositol 3-kinase. Exposure of human umbilical vein endothelial cells to Ang II elicited a rapid phosphorylation of Akt and FoxO1, a known target of Akt signaling. Constitutively active Akt inhibits the activity of the hSR-BI/CLA-1 promoter, and a dominant-negative mutant of Akt or mutagenesis of a FoxO1 response element in the hSR-BI/CLA-1 abolished the ability of Ang II to suppress promoter activity. Together, these results indicate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway participates in Ang II suppression of hSR-BI/CLA-1 expression and suggests that the endothelial receptor for hSR-BI/CLA-1 is downregulated by the renin–angiotensin system.
Key Words: angiotensin II • hSR-BI/CLA-1 • HDL • Akt • FoxO1 • HUVEC
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Introduction |
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High-density lipoprotein (HDL) particles play a critical role in cholesterol metabolism because they mediate a normal physiological process, so-called reverse cholesterol transport.1,2 In this process, HDL particles shuttle cholesterol from extrahepatic tissues to the liver for further metabolism and excretion.1 Enhanced reverse cholesterol transport lowers total body cholesterol and thereby reduces the risk of developing coronary artery disease. Thus, the plasma concentration of HDL is inversely related to the incidence of coronary artery disease.3 The mouse scavenger receptor class BI (SR-BI) mediates selective uptake of HDL cholesterol ester into transfected Chinese hamster ovary cells. This finding provides an important link between a specific cell surface receptor and a pathway for the uptake of HDL.4 Our previous reports show that human homologue of SR-BI, CD36, and LIMPII analogous-1 (hSR-BI/CLA-1), like mouse SR-BI, functions as a receptor for HDL.5,6 However, the mechanisms by which HDL is atheroprotective are complex and not well understood.
Endothelial dysfunction plays a pivotal role in the initiation and progression of atherosclerosis. In fact, the vascular endothelium modulates the vessel tone by releasing both relaxing and contractile factors,7 regulates the adherence of mononuclear cells to its surface and the vascular permeability,8,9 and produces substances involved in the regulation of hemostasis and tissue proliferation.10 The release of NO by endothelial NO synthase (eNOS) is important in the regulation of cardiovascular homeostasis. Recent reports indicated that SR-BI and eNOS are colocalized in vascular endothelial cells. Thus, HDL activates eNOS via SR-BI, and the resulting increase in NO production might be critical to the atheroprotective properties of HDL.11–13 Angiotensin II (Ang II), the key effector of the renin–angiotensin system, plays a central role in the regulation of vascular tone, blood pressure, and electrolyte homeostasis.14 Ang II mediates its effects via binding to specific receptors on the cell surface. Ang II receptors of the cardiovascular system are divided into 2 main subtypes: Ang II type-1 (AT1) and type-2 (AT2) receptors.15 It is well known that Ang II modulates NO production in human umbilical vein endothelial cells (HUVECs).16 In the present study, we have examined the role of Ang II on hSR-BI/CLA-1 expression in HUVECs to clarify the effect of Ang II on HDL-mediated NO synthase (NOS) activity.
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Methods |
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An expanded Methods section is available in an online supplement at http://hyper.ahajournals.org.
Measurement of NOS Activity
Release of NO from endothelial cells for 6 minutes after the addition of HDL was examined by the measurement of nitrite in the supernatant (phenol red free) with an automated NO detector–high-performance liquid chromatography system (ENO-20, Eicom Co, Ltd). Nitrite was separated by a column (NO-PAK packed with polystyrene polymer, 4.6x50 mm; Eicom), mixed with a Griess reagent to form a purple azo dye in a reaction coil, and detected by absorption at 540 nm as a single peak. The mobile phase, which was delivered by a pump at a rate of 0.33 mL/min, was 10% methanol containing 0.15 mol/L of NaCl-NH4Cl and 0.5 g/L of tetrasodium EDTA. The Griess reagent, which was 1.25% HCl containing 5 g/L of sulfanilamide with 0.25 g/L of N-naphthylethylenediamine, was delivered at a rate of 0.1 mL/min.
Plasmid Preparation
An expression vector encoding a constitutively active Akt and a dominant-negative mutant of Akt (Akt-DN) was described previously.17 The reporter construct contained the hSR-BI/CLA-1 gene sequence spanning the region from –1200 to +2 as determined from the published sequence.18 The segment of interest was amplified using PCR and cloned into the luciferase reporter gene (pCLA-LUC). To generate the mutant construct (pCLAmFRS-LUC) of the FOXO1 response sequence (FRS) within the vector, pCLA-LUC was mutated from –1110 5'-GTCATTCATTCTAGAATATTTACTGT GAGCAGGCATTCCCTGCC-3' –1066 to 5'-GTCATTCATTCT AGAATAGGGACTGTGAGCAGGCATTCCCTGCC-3' (mutated nucleotides are italicized) by site-directed mutagenesis as reported previously.17 Expression vectors for FOXO1 proteins have been reported previously.19
Transfection of HUVECs and Luciferase Reporter Gene Assay
Purified reporter plasmid was transfected into HUVECs using a conventional cationic liposome transfection method (Lipofectamine, Life Technologies). All of the assays were corrected for ß-galactosidase activity, and the total amount of protein in each reaction was identical. Twenty-microliter aliquots were taken for the luciferase assay, which was performed according to the manufacturer’s instructions (ToyoInk).
Immunoblot of Akt and FoxO1
Akt phosphorylated at Thr308 and FoxO1 phosphorylated at Ser256 were detected by using a phosphospecific Akt polyclonal antibody (diluted 1:500, Upstate Biotechnology), a phosphospecific FoxO1 polyclonal antibody (diluted 1:1000, Cell Signaling), and total Akt (diluted 1:500, Upstate Biotechnology). FoxO1 (diluted 1:1000, Cell Signaling) was detected by using phosphorylation-independent antibodies (Upstate Biotechnology).
Statistical Analysis
Statistical comparisons were made possible through the use of 1-way ANOVA and Student’s t test, with P<0.05 considered significant.
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Results |
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Ang II Decreases hSR-BI/CLA-1 Expression in HUVECs
To analyze the effects of Ang II on hSR-BI/CLA-1 expression, we measured the levels of endogenous hSR-BI/CLA-1 expression in HUVECs using Western blot analysis. Exposure of these cells to Ang II decreased the abundance of endogenous hSR-BI/CLA-1 protein in a dose-dependent manner as compared with that in cells maintained in control medium (Figure 1). Furthermore, the abundance of hSR-BI/CLA-1 mRNA also decreased after treatment with Ang II (Figure S1). The result showed a maximal effect at 24 hours, which appeared to show a reversal trend at 48 hours after Ang II treatment. These results show clearly that Ang II inhibits the expression of hSR-BI/CLA-1 in HUVECs.
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Effect of Ang II on hSR-BI/CLA-1 Promoter Activity
The preceding observations prompted us to measure transcriptional activity of the hSR-BI/CLA-1 promoter in the HUVECs. Therefore, the response of pCLA-LUC activity to Ang II was tested in HUVECs. Consistent with the observed changes in the levels of hSR-BI/CLA-1 protein and mRNA, Ang II inhibited activity of the promoter in a dose-dependent manner. The maximal effect was observed at 100 nM of Ang II in HUVECs (data not shown).
Next we tested whether protein kinases were involved in Ang II–mediated inhibition of hSR-BI/CLA-1 promoter activity. To address this question, we studied the effect of pharmacological inhibitors on hSR-BI/CLA-1 promoter activity. In this study, Ang II stimulation (100 nM) was added in combination with phosphatidylinositol 3-kinase (PI3K) inhibitors (10 µmol/L of wortmannin, LY294002); a mitogen-activated extracellular signal-regulated kinase inhibitor (10 µmol/L of PD98059), a protein kinase A inhibitor, H-89 (H); a selective inhibitor of Ca2+/calmodulin-dependent protein kinase, STO-609; and a protein kinase C (10 µmol/L of bisindolylmaleimide I) to the HUVECs. Results (Figure 2) showed that the inhibitory effect of Ang II on hSR-BI/CLA-1 promoter activity was not sensitive to inhibitors of the extracellular signal-regulated kinase, protein kinase A, calmodulin-dependent protein kinase, and protein kinase C, but it was sensitive to wortmannin and LY294002, an inhibitor of PI3K. Furthermore, the inhibitory effect of Ang II on hSR-BI/CLA-1 mRNA was cancelled by treatment with LY294002 (Figure S2). This finding suggests that the actions of Ang II appear to be mediated by PI3K.
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Time Course of Akt Phosphorylation by Ang II
The preceding studies show that PI3K may be required for the inhibitory effects of Ang II on hSR-BI/CLA-1 expression. Because Akt is a potential target of the PI3K, we wondered whether Ang II activated the Akt kinase. This possibility led us to examine the kinetics of Akt activation by measuring its ability to phosphorylate residues Thr308 and Ser473 of the protein. These modifications are a prerequisite for catalytic activity of Akt. The results (Figure 3A) showed that Akt phosphorylation was evident within 5 minutes after exposure of the HUVECs to Ang II, and this activity reached a peak at 15 minutes.
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Akt Regulates hSR-BI/CLA-1 Promoter Activity
Because Akt phosphorylation participates in Ang II inhibition of hSR-BI/CLA-1 expression, we asked whether Akt affected hSR-BI/CLA-1 promoter activity. If so, then the actions of constitutively active Akt should affect activity of the promoter. As predicted, the results (Figure 3B) showed that constitutively active Akt suppressed hSR-BI/CLA-1 promoter activity in HUVECs. We asked whether a dominant-negative mutant of Akt (Akt-DN) had an effect on hSR-BI/CLA-1 promoter activity (Figure 3B). As expected, the expression of Akt-DN inhibited the actions of Ang II on hSR-BI/CLA-1 promoter activity. Furthermore, the transfection of Akt-DN cancelled the effect of Ang II on hSR-BI/CLA-1 expression but not on AT1 receptor expression (Figure S3).
Effect of Ang II on HDL-Mediated NOS Activity
A previous report indicated that HDL binding to SR-BI/CLA-1 activates eNOS.11 Because the current studies show that Ang II inhibited the expression of SR-BI/CLA-1 in HUVECs, we wondered whether HDL-SR-BI/CLA-1–mediated NOS activity would be modulated by Ang II treatment. This possibility led us to examine the effect of Ang II on HDL-mediated NOS activity in HUVECs. HDL stimulated eNOS activation in HUVECs, which is consistent with the previous observations.11–13 Treatment with HDL induced the eNOS activation that was blocked by a pretreatment with a competitive L-arginine analogue (NG-nitro-L-arginine methyl ester). In this study, we incubated the cells with Ang II before HDL stimulation. In Ang II–treated cells, HDL did not activate NOS activity (Figure 4). Results also show that Ang II treatment alone decreased NOS activity compared with that of control cells; however, the inhibitor LY294002 did not cancel the effect of Ang II-suppressed basal NOS activity. Further studies will be needed to clarify the effect of Ang II on basal NOS activity.
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Ang II Inhibited hSR-BI/CLA-1 Expression by Stimulation of the AT1 Receptor
To investigate the mechanism of Ang II on hSR-BI/CLA-1, we examined the role of its main receptor, AT1. Olmesartan medoxomil is a prodrug that is rapidly metabolized to the pharmacologically activated form, RNH-6270. Therefore, we used RNH-6270 for the in vitro experiments. The expression of hSR-BI/CLA-1 was inhibited by Ang II in dose-dependent manners (Figure 1). The AT1 receptor antagonist RNH-6270 attenuated the effects of Ang II on hSR-BI/CLA-1 expression in a dose-dependent manner (Figure 5A) and also on hSR-BI/CLA-1 promoter activity (Figure 5B). In contrast, the AT2 receptor inhibitor PD 123319 was unable to modify the Ang II actions on hSR-BI/CLA-1 expression (data not shown).
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FoxO1 Regulates the hSR-BI/CLA-1 Expression
FoxO1 is a member of the FoxO subgroup forkhead-type transcription factors that contain a unique insert of 5 amino acids in the highly conserved forkhead box (or Fox box) DNA-binding domain and 3 putative phosphorylation sites for the Ser/Thr kinase Akt. Because FoxO1 might be a target of Akt in HUVECs, we postulated that Ang II should increase phosphorylation of FoxO1 in HUVECs. FoxO1 phosphorylation was apparent within 5 minutes after stimulation by Ang II (Figure 6A). FoxO1 has different target genes, and there is a consensus sequence, TT[G/A]TTT[T/A][G/C] in their promoters.20 We identified a putative FRS on hSR-BI/CLA-1 promoter by searching the BLASTN program in a genomic database. To determine whether FoxO1 may have an important role on the Ang II–suppressed hSR-BI/CLA-1 transcription in HUVECs, we created a construct, pCLAmFRS-LUC, that contained a mutated putative FRS (5'-TTT to 5'-GGG). Studies (Figure 6B) showed that cotransfection of FoxO1 stimulates the activity of the wild-type pCLA-LUC promoter construct and that mutation of the FRS (pCLAmFRS-LUC) disrupts this effect of FoxO1. Finally, FRS mutation dramatically reduces the ability of Ang II to stimulate hSR-BI/CLA-1 promoter function (Figure 6C). These results indicate that Ang II inhibited the hSR-BI/CLA-1 promoter activity gene via the FRS in HUVECs.
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Discussion |
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Recent work has shown that HDL has novel actions in endothelium to promote the production of the atheroprotective signaling molecule NO.11–13 We also now know that the high-affinity HDL receptor SR-BI is required and that this process is mediated by kinase cascades that converge to regulate the activity of eNOS. The kinases involved include Akt (also known as protein kinase B), protein kinase A, protein kinase C, and calmodulin-dependent kinase II.21 Previous reports showed that HDL stimulates the phosphorylation of eNOS at serine-1179, whereas HDL has no effect on the phosphorylation of threonine-497. HDL-induced phosphorylation of eNOS is mediated by Akt kinase, because the expression of a dominant-negative Akt mutant attenuates the effect of HDL on the enzyme.13 A previous study reports that patients with elevated HDL have greater vasodilator and attenuated vasoconstrictor responses.22 In addition, endothelial function is enhanced in hypercholesterolemic men with normal HDL levels shortly after the administration of apolipoprotein A-I/phosphatidylcholine particles.23 These observations indicate that HDL is a positive modulator of endothelial NO generation in humans. Further clinical investigations will be needed to clarify the mechanisms by which HDL has direct endothelial actions.
One of the goals of the present study was to examine in more detail signaling pathways activated by Ang II in HUVECs. These include 2 substrates of Akt, as well as FoxO1. The FoxO subfamily of forkhead transcription factors is a downstream target of Akt. This subfamily consists of 3 members, FoxO1, FoxO3a (FoxO1L-1), and FoxO4 (AFX), which are all inactivated by Akt.24,25 Phosphorylation by Akt leads to nuclear exclusion and the inhibition of the forkhead transcriptional program. FoxO transcription factors have been implicated in regulating diverse cellular functions including differentiation, metabolism, proliferation, and survival.26,27 The activity of the FoxO1 family is known to be regulated by PI3K-activated signal transduction pathway, as has been observed in many systems.28 The PI3K pathway was initially implicated when cultured cells were treated with growth factors (ie, epithelial growth factor, insulin-like growth factor I, and insulin) that are known to activate the PI3K pathway, and FoxO1 is shown to be excluded from the nucleus. Additional studies demonstrated that removal of growth factors resulted in the accumulation of FoxO1 protein in the nucleus. Furthermore, it is well acknowledged that Akt mediates many of the effects of growth factors downstream of PI3K,29 and several FoxO1 proteins are now established substrates of Akt in this pathway.25,30,31 In the hSR-BI/CLA-1 promoter, there are a number of consensus-binding motifs for transcription factors.32 Our results indicate that the PI3K/Akt pathway regulates the expression of hSR-BI/CLA-1 and that this effect is mediated through FoxO transcription factors. Reporter gene studies demonstrate that FoxO proteins stimulate hSR-BI/CLA1 promoter activity through this site and that this FoxO site is required for the effect of Ang II and Akt on promoter function. The mutation of this site on hSR-BI/CLA-1 cancelled the effect of Ang II, raising the possibility that the PI3K/Akt/FoxO1 pathway might mediate the effect of Ang II on the hSR-BI/CLA-1 gene. Further studies will be needed to determine the detailed mechanisms involved in the regulation of the SR-BI/CLA-1 gene.
Our recent report revealed that the C-terminal tail of hSR-BI/CLA-1 might play an important role on HDL-mediated signal transduction mechanisms including the PI3K/Akt signaling pathway.33 We expect that the coupling might involve intermediary proteins such as CLAMP, a protein containing 4 PDZ domains that associates with the extreme C terminus of SR-BI.34 In this report, our results demonstrated that the PI3K/Akt pathway enhanced by Ang II suppressed the expression of hSR-BI/CLA-1. The data presented here suggest the model in which the PI3K/Akt signaling pathway regulates hSR-BI/CLA-1 expression through the phosphorylation of FoxO transcriptional factor. In this model, the absence of PI3K signaling results in FoxO activation and increased expression of hSR-BI/CLA-1. This regulation suggests the interesting possibility of a negative feedback loop in which PI3K/Akt signaling is activated by HDL via hSR-BI/CLA-1, leading to inactivation of FoxO1 and downregulation of hSR-BI/CLA-1.
A recent report indicates that Ang II inhibits cell migration by reducing NO availability, and such Ang II–related decrement in NO availability is attributable to an AT1-dependent increment in oxidant generation by cultured HUVECs.16 Several pharmacological interventions have been developed to attenuate Ang II vascular effects. In particular, inhibition of Ang II synthesis and, subsequently, blocking of its high-affinity subtype-1 (AT1) have allowed the targeting of Ang II–dependent negative effects.35 The inhibition of hSR-BI/CLA-1 by Ang II can be completely prevented by AT1 receptor blockade. This finding suggests an antiatherosclerotic potential of pharmacological interventions in the rennin–angiotensin system.
Perspectives
PI3K–Akt–FoxO1 pathways participate in Ang II suppression of SR-BI/CLA-1 expression and suggest that the endothelial receptor for hSR-BI/CLA-1 is downregulated by the renin–angiotensin system. The upregulation of Ang II–inhibited hSR-BI/CLA-1 expression might represent a novel mechanism contributing to the antiatherosclerotic potential of AT1 receptor blockade in vascular endothelial cells.
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Acknowledgments |
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We thank Kazuko Yamaji and Kiyo Ueeda for their technical assistance.
Sources of Funding
This work was supported in part by Grant-in-Aid for Scientific Research 14770601 (K.Murao) and Grant-in-Aid for Scientific Research 15590944 (T.I., K.Murao).
Disclosures
None.
Received October 10, 2006; first decision October 30, 2006; accepted March 8, 2007.
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