Published online before print December 24, 2007, doi: 10.1161/HYPERTENSIONAHA.107.099028
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(Hypertension. 2008;51:259.)
© 2008 American Heart Association, Inc.
Original Articles |
Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-
From the Department of Internal Medicine II-Cardiology (D.W., K.H., P.H., K.P., D.V., K.R., V.H., N.M.), University of Ulm, Ulm, Germany; and the Center for Cardiovascular Research (U.K., M.C., M.H.), Institute of Pharmacology and Toxicology, Charite-Universitatsmedizin Berlin, Berlin, Germany.
Correspondence to Nikolaus Marx, Department of Internal Medicine II-Cardiology, University of Ulm, Robert-Koch-Str 8, D-89081 Ulm, Germany. E-mail nikolaus.marx{at}uniklinik-ulm.de
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Abstract |
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Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-
–activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPAR in this context. CD4-positive lymphocytes express both the AT1R and PPAR. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1±3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6±0.7-fold induction at 10 µmol/L of telmisartan (P<0.01 compared with SDF-1–treated cells; n=22). Three different PPAR activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPAR–activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan’s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPAR small interfering RNA abolished telmisartan’s effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPAR. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPAR-activating properties.
Key Words: telmisartan • PPAR • angiotensin type 1 receptor blocker • CD4-positive lymphocytes • migration
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Introduction |
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Atherogenesis is an inflammatory process in the vessel wall involving inflammatory cells like monocytes, macrophages, and CD4-positive lymphocytes.1 In early atherogenesis, CD4-positive lymphocytes are attracted by chemotactic proteins, such as regulated upon activation, normal T-cell expressed, and secreted (RANTES) and stromal cell-derived factor (SDF)-1 and enter the vessel wall as naïve T-helper 0 cells. In the subendothelium, these cells then encounter antigens like oxidized low-density lipoprotein and differentiate into T-helper 1 cells, subsequently releasing proinflammatory mediators like tumor necrosis factor-
and interferon-. These cytokines then govern the inflammatory response in the vessel wall by activating other cells, such as endothelial cells, macrophages, and vascular smooth muscle cells, thus promoting the inflammatory process in atherogenesis. It is unclear whether an inhibition of cell migration itself modulates vascular disease, but various experimental studies have shown that a reduction in CD4-positive lymphocyte recruitment hampers lesion development and plaque formation.2,3 Still, most of these studies targeted the effect of T-cell–specific chemokines, but hitherto little is known about modulatory effects on CD4-positive lymphocyte migration.
Telmisartan is an angiotensin-II type 1 receptor (AT1R) blocker, currently used to treat patients with hypertension.4 Recent data suggest that telmisartan, in addition to its effect on the AT1R, can activate the nuclear transcription factor peroxisome proliferator-activated receptor- (PPAR),5–13 thus acting as a partial PPAR agonist. PPAR is involved in the regulation of glucose homeostasis, insulin resistance, and lipoprotein metabolism, and activators of PPAR, like the antidiabetic thiazolidinediones (TZDs) rosiglitazone or pioglitazone, are in clinical use as antidiabetic agents.14 Furthermore, recent data suggest that PPAR is expressed in CD4-positive lymphocytes and that activation of PPAR by TZDs reduces inflammatory T-cell activation,15,16 as well as C-peptide–induced T-cell chemotaxis.17 However, to date, the effect of telmisartan or any other PPAR activator on chemokine-induced CD4-positive lymphocyte migration is unexplored. Therefore, the current study examined the effect of telmisartan on CD4-positive lymphocyte migration and investigated to what extent a modulatory function of telmisartan on cell migration may be mediated by its PPAR-activating properties.
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Methods |
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Cell Culture
Human CD4-positive lymphocytes were isolated from the freshly drawn blood of healthy volunteers by Ficoll-Histopaque (Sigma) gradient centrifugation to obtain peripheral blood mononuclear cells and subsequent negative selection of CD4-positive T cells by magnetic bead separation (Miltenyi Biotech), as described by the manufacturer’s protocol. The purity of CD4-positive T cells was >97% as determined by flow cytometry.
In Vitro Cell Migration Assay
After isolation, CD4-positive cells were cultured in serum-free medium for 16 hours. T-cell chemotaxis was assayed under serum-free conditions in a 48-well microchemotaxis chamber (Neuroprobe). Wells in the upper and lower chambers were separated by a polyvinylpyrrolidone-free polycarbonate membrane (pore size: 5 µm; Costar). CD4-positive cells at a density of 5x105/mL were pretreated for 15 minutes with the AT1R antagonists telmisartan or eprosartan or with the PPAR activators rosiglitazone, pioglitazone, or GW1929 before 3 hours of incubation with SDF-1 or RANTES (Sigma). Migrated cells on the bottom face of the filter were stained and counted under the light microscope. Cells were counted in 5 random high-power fields per well.
Western Blot Analysis
Standard Western blot analysis was performed using mouse anti-human AT1R antibodies (Upstate).
Transfection of Small Interfering RNA
Specific and negative small interfering RNAs (siRNAs) were purchased from Invitrogen. PPAR siRNAs refer to PPAR Validated Stealth RNAi DuoPak. Negative siRNA refers to Negative Control Validated Stealth (Invitrogen) and has no homology to any known human gene sequence. siRNA transfection was performed using human CD4-positive lymphocytes. Cells were isolated from blood and incubated for 1 hour in RPMI medium 1640 with 5% human serum. T cells were transfected with PPAR siRNA (100 nM) using the human T-cell nucleofector kit (Amaxa Biosystems) according to the manufacturer’s protocol. After transfection, cells were plated in 12-well plates with RPMI medium 1640 containing 5% human serum and incubated for 48 hours. Untreated cells, amaxa nucleofector solution, and negative siRNA controls were established in parallel. To assess the role of telmisartan in mock- or PPAR siRNA-transfected T-cells, we used intercellular adhesion molecule (ICAM)-3 translocation as a readout for cell migration, because both mock- and siRNA-transfected cells no longer exhibit a full chemotactic response in our chemotaxis assay (data not shown), most likely because of the fact that the transfection procedure itself interferes with other parts of the migration machinery.
Phosphatidylinositol Kinase Assay
After isolation, human T cells were incubated for 16 hours in RPMI medium 1640 without serum. Cells pretreated for 15 minutes with or without telmisartan or any other PPAR activator were stimulated with 100 ng/mL of SDF-1. Standard phosphatidylinositol 3-kinase (PI3K) activity assays were performed17 using goat anti-human p85 (Santa Cruz) antibodies.
F-Actin Staining
CD4-positive lymphocytes (2x106 cells/mL) were treated with SDF-1 at 100 ng/mL for times indicated after 15 minutes pretreatment with different inhibitors (telmisartan, rosiglitazone, pioglitazone, and GW1929). After stimulation cells were fixed in 3.7% (wt/vol) paraformaldehyde in PBS (pH 7.4) and then washed at room temperature in Tris-buffered saline (50 mmol/L of Tris-HCl [pH 7.6], 150 mmol/L NaCl, and 0.1% NaN3). For intracellular staining of F-actin cells were permeabilized with 0.1% Triton X-100 for 10 minutes before application of the first antibody. Cell suspensions were incubated for 30 minutes in PBS with fluorescein isothiocyanate–conjugated phalloidin (Sigma P5282). Flow cytometry analysis was performed in a FACScan cytofluorometer (Becton Dickinson), and induction of F-actin was measured.
ICAM3 Staining
Immunofluorescence staining was performed as described before.17 In brief, 1 to 2x106 CD-4 positive lymphocytes were incubated in special 4-well plates (Costar Corp) in a final volume of 500 µL of complete medium on coverslips coated with collagen. Before treatment with SDF-1 (100 ng/mL for 30 minutes), cells were incubated with telmisartan, rosiglitazone, pioglitazone, or GW1929 for 15 minutes. Cells were then fixed with 3.7% (wt/vol) paraformaldehyde in PBS (pH 7.4) at room temperature and rinsed in Tris-buffered saline. Cells were incubated with a specific antibody against ICAM3 (mouse anti-human ICAM3, Caltag), and after washing with PBS, carboxymethylindocyanine 3-Cy3-coupled (Dianova) goat anti-mouse IgGs were added as secondary antibodies (dilution: 1:1000) for 45 minutes. After washing again, slides were stained with 4',6-diamidino-2-phenylindole (DAPI; nuclei staining). Images were recorded with a fluorescence microscope (Leica), and cells in 5 randomly selected fields (
100 cells) were analyzed. ICAM-3 translocation was considered to be present when a clear clustering of ICAM3 at the uropod was visible.
Statistical Analysis
Results of the experimental studies are reported as mean±SD. Differences were analyzed by 1-way ANOVA followed by the appropriate posthoc test. A P value <0.05 was regarded as significant.
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Results |
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CD4-Positive Lymphocytes Express AT1Rs
Western blot analysis revealed that isolated human CD4-positive lymphocytes express AT1R protein (Figure 1A). In addition, RT-PCR demonstrated AT1R mRNA expression (data not shown).
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Telmisartan Reduces CD4-Positive Lymphocyte Migration
To examine the effect of telmisartan on CD4-positive lymphocyte migration, cells were stimulated with SDF-1 in the absence or presence of telmisartan, and lymphocyte migration was assessed in a modified Boyden chamber. SDF-1 treatment significantly induced cell migration by 4.1±3.1-fold (P<0.01; n=22), and pretreatment of cells with telmisartan for 15 minutes reduced this effect in a concentration-dependent manner to a maximal 1.6±0.7-fold induction at 10 µmol/L of telmisartan (P<0.01 compared with SDF-1 treated cells; n=22; Figure 1B). Similar effects were obtained when RANTES was used as a stimulus to induce CD4-positive lymphocyte migration (data not shown), suggesting that telmisartan’s action on lymphocyte migration is independent of the stimulus used. Treatment of cells with telmisartan at the time of SDF-1 stimulation or treatment 15 minutes after the addition of SDF-1 did not result in a significant reduction of chemokine-induced cell migration (data not shown).
Next we investigated the effect of the non-PPAR–activating AT1R antagonist eprosartan8 on CD4-positive lymphocyte migration. As shown in Figure 1C, eprosartan did not significantly influence SDF-1–induced cell migration, suggesting that telmisartan’s effect on CD4-positive cell migration may be independent of the AT1R.
PPAR Activators Reduce CD4-Positive Lymphocyte Migration
Because telmisartan, a known activator of PPAR, reduced CD4-positive lymphocyte chemotaxis, whereas the non-PPAR–activating AT1R blocker eprosartan did not exhibit such effects, we next examined whether other well-established PPAR activators influenced cell migration. Two PPAR-activating TZDs, rosiglitazone and pioglitazone, significantly reduced SDF-1- (Figure 2A) and RANTES-induced CD4-positive lymphocyte migration in a concentration-dependent manner (Figure 2B). In addition, the non-TZD PPAR activator GW1929 had similar effects on SDF-1- (Figure 2C) and RANTES-induced cell chemotaxis. These data suggest that PPAR activation can inhibit chemokine-induced CD4-positive lymphocyte migration, potentially providing an explanation for the effects observed with telmisartan.
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Telmisartan Limits PI3K Activity in CD4-Positive Lymphocytes
Activation of PI3K is a critical step in chemokine-induced T-cell migration downstream of the respective chemokine receptor.18 Therefore, we examined the effect of telmisartan on PI3K activity. As demonstrated in Figure 3A, telmisartan significantly limited SDF-1–induced PI3K activity. Moreover, rosiglitazone, pioglitazone, and GW1929 had similar effects (Figure 3B). These data suggest that telmisartan, as well as other PPAR activators, modulates a very upstream step of the chemokine-activated signaling cascade.
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Telmisartan Reduces F-Actin Formation in CD4-Positive Lymphocytes
Next we investigated the effect of telmisartan on F-actin formation in CD4-positive lymphocytes, a crucial mechanism in cell polarization during migration.19,20 Telmisartan significantly reduced SDF-1–induced F-actin formation, as demonstrated by flow cytometry (Figure 4A). Similarly, rosiglitazone and pioglitazone, as well as GW1929, also decreased SDF-1–induced F-actin formation (Figure 4B and 4D), but the results for pioglitazone were borderline significant.
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Telmisartan Inhibits ICAM3 Translocation in CD4-Positive Lymphocytes
Because ICAM3 translocation at the uropod of migrating lymphocytes is a critical step in cell movement,21 we next examined the effect of telmisartan, as well as other PPAR activators, on ICAM3 translocation by means of immunofluorescence staining. Telmisartan, pioglitazone, and rosiglitazone, as well as GW1929, significantly diminished SDF-1–induced ICAM3 translocation (Figure 5).
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Telmisartan Exhibits Its Effects on CD4-Positive Lymphocytes Independent of the AT1R via PPAR
To investigate whether telmisartan’s actions on cell migration and ICAM3 translocation are independent of the AT1R, we pretreated human CD4-positive lymphocytes with high doses of eprosartan to block AT1Rs and then evaluated the effect of telmisartan on SDF-1–induced migration. As shown in Figure 6A, eprosartan pretreatment of cells at concentrations known to block the AT1R22 did not affect telmisartan’s inhibitory effect on SDF-1–induced migration. Similarly, blockade of the AT1R by eprosartan did not hamper the reduction of ICAM3 translocation by telmisartan, suggesting an effect of telmisartan independent of the AT1R (Figure 6B).
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Finally, we examined the effect of telmisartan on SDF-1–induced ICAM3 translocation in PPAR-negative cells as achieved by PPAR siRNA transfection. Mock and PPAR siRNA-transfected cells (Figure 7A) did not differ with respect to AT1R expression (Figure 7B), but in PPAR-negative cells, telmisartan did not inhibit SDF-1–stimulated ICAM3 translocation (Figure 7C and 7D). Taken together, these data suggest that telmisartan exhibits its effects on CD4-positive lymphocyte migration and ICAM3 translocation via PPAR.
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Discussion |
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The present study demonstrates that telmisartan inhibits chemokine-induced migration of CD4-positive lymphocytes by reducing PI3K activity with subsequent inhibition of F-actin formation and ICAM3 translocation. These effects of telmisartan on cell migration are mediated by PPAR
and independent of the AT1R.
CD4-positive lymphocytes express AT1R mRNA and protein as demonstrated in this study, and previous work from our group has shown the expression of PPAR in these cells.16 Telmisartan is an AT1R blocker, clinically used to treat patients with hypertension, which, in addition to its effect on the AT1R, has been shown to exhibit PPAR-activating properties.6,8 Still, previous studies only examined PPAR-mediated metabolic effects of telmisartan, as well as effects on adipocyte differentiation and adipocyte gene expression. Our data now suggest that telmisartan exhibits PPAR-dependent anti-inflammatory effects, as described previously for other PPAR activators, like the antidiabetic TZDs. These drugs, in addition to their action on insulin sensitivity and glucose homeostasis, exhibit anti-inflammatory and anti-atherogenic properties in vitro and in vivo (reviewed in Reference 23). As such, TZDs inhibit inflammatory activation of endothelial cells, monocyte/macrophages, and vascular smooth muscle cells, as well as CD4-positive lymphocytes. Experimental studies revealed that PPAR-activating TZDs modulate important processes in atherogenesis, like cytokine and chemokine release, matrix metalloproteinase expression, and cell proliferation. In CD4-positive lymphocytes, PPAR activators have been shown to limit T-helper 1 cytokine expression, suggesting a modulatory effect on inflammatory cell activation at a nodal point of lesion development. Our data now extend the current knowledge of PPAR activator’s action in these cells by demonstrating a reduction of chemokine-induced T-lymphocyte migration.
The effect of telmisartan on lymphocyte migration is independent of the AT1R but mediated via PPAR: first, eprosartan, a non-PPAR–activating AT1R antagonist, did not affect chemokine-induced cell migration, whereas 3 different well-established PPAR activators, the TZDs rosiglitazone and pioglitazone, as well as the non-TZD PPAR activator GW1929, exhibited antichemotactic action similar to telmisartan. Second, blockade of the AT1R by high concentrations of eprosartan did not hamper telmisartan’s effect on cell migration. Finally, downregulation of PPAR expression by siRNA transfection abolished the effect of telmisartan on chemokine-induced ICAM3 translocation as a readout for cell migration. Our data are limited to this surrogate of cell migration, because the transfection procedure itself seems to interfere with other targets in the migration machinery, thus making both mock- and siRNA-transfected cells irresponsive to chemokine stimulation in the migration assay. Still, because ICAM3 translocation is a well-established readout for cell migration, our data suggest that telmisartan does not require functional AT1Rs to inhibit T-cell migration and that blockade of the AT1R itself does not affect lymphocyte chemotaxis. With respect to PPAR, previous work in monocytes has shown that PPAR activators can modulate cell migration,24 suggesting that this pathway may be involved in the inhibition of mononuclear cell migration in general.
The telmisartan concentrations in our experiment may be higher than maximum plasma concentrations achieved in treated patients.25,26 Still, the concentrations used here correspond with the concentrations used in previous experiments investigating PPAR-activating properties of telmisartan. In addition, telmisartan is a very lipophilic agent, and the biological action in the tissue does not necessarily correlate with plasma concentrations. Future studies are warranted to examine whether therapeutic doses of telmisartan are sufficient to modulate T-cell function in vivo.
Chemokine-induced T-cell migration is mediated by activation of G-protein–coupled receptors leading to an increase in PI3K activity18 with subsequent polarization of cells and formation of a leading edge and the so called uropod in the rear.20 The agonists used in our study interfere with this signaling pathway by inhibiting PI3K activity. Interestingly, 15-minute pretreatment of CD4-positive cells with telmisartan or TZDs already prevented the rapid effect of SDF-1 on PI3K activation, raising the question of a nontranscriptional effect of these agents in this context, as suggested before.27 Previous studies in smooth muscle cells did not find such an effect of the non-PPAR–activating AT1R antagonist losartan on PI3K activation, suggesting the possibility of an AT1R-independent action of telmisartan.28 Downstream of PI3K, telmisartan leads to a reduction in F-actin formation and ICAM3 translocation at the uropod of the cell, thus counterbalancing critical steps in cell movement. In addition, the effect of telmisartan and other PPAR activators on cell migration does not depend on the chemotactic stimulus, because all substances used diminished both SDF-1- and RANTES-induced lymphocyte migration. Recent work on PPAR-mediated effects of telmisartan has mainly focused on its metabolic action, including effects on adipocyte differentiation, expression of genes involved in insulin sensitivity, and fatty acid metabolism, as well as the modulation of glucose homeostasis.6,8,9 These metabolic effects of telmisartan are similar to what has been shown with PPAR-activating TZDs. Our data now suggest that telmisartan, via PPAR, also exhibits anti-inflammatory effects in vascular cells, as described previously for TZDs. As such, telmisartan may not only interfere with the renin-angiotensin system but may also influence vascular inflammation by its PPAR-activating properties.
The inhibition of lymphocyte migration shown here may influence atherogenesis at a critical step. CD4-positive cells, once recruited into the subendothelial space by chemokines like SDF-1 or RANTES, differentiate to T-helper 1 cells, thus releasing proinflammatory cytokines, which then promote inflammatory activation of other cells in the vessel wall.1 So far, there are no data showing that an inhibition of T-cell migration directly influences atherogenesis, but various groups have demonstrated that a reduction of the expression of T-cell–specific chemokines hampers plaque formation.2,3 Thus, it may be assumed that modulating the migration of T-lymphocytes into the vasculature may also target the inflammatory process in atherogenesis at a nodal point and, as such, address a critical step in lesion development. Still, recent data by Ait-Oufella et al29 have shown that a subset of CD4-positive lymphocytes, named natural regulatory cells (CD4+/CD25+ regulatory T cells), may exhibit atheroprotective effects, raising the question of whether an inhibition of CD4-lymphocyte migration may be protective under all circumstances. Therefore, future studies are warranted to determine whether such effects of telmisartan via PPAR finally lead to a reduction in lesion size in animal models of arteriosclerosis.
Perspectives
Partial activation of PPAR by selective PPAR modulators (SPPARMs) is an emerging concept designed to obtain beneficial PPAR effects without adverse effects. PPAR is involved in the regulation of glucose homeostasis, insulin resistance, and lipoprotein metabolism, and activators of PPAR, like the antidiabetic TZDs rosiglitazone or pioglitazone, are in clinical use as antidiabetic agents. Furthermore, PPAR activators have been shown to mediate anti-inflammatory effects in the vasculature. Still, in clinic, these agents do have unwanted adverse effects, like fluid retention and weight gain, underscoring the potential benefit of SPPARMs. Recent work has established that the AT1R blocker telmisartan can act as a SPPARM, thus regulating gene expression in a PPAR-dependent manner, eg, in adipocytes. Moreover, telmisartan mediates beneficial metabolic effects in vivo. Our data suggest that telmisartan also exhibits anti-inflammatory effects in CD4-positive lymphocytes by inhibiting chemokine-induced cell migration, a critical step in atherogenesis. Such anti-inflammatory and antiatherogenic properties of telmisartan raise the hypothesis that SPPARMs may not only have beneficial effects in metabolic disorders, like insulin resistance and diabetes, but could also be used to modulate vascular disease. Still, future studies in animal models are needed to prove whether this concept holds true in vivo, and subsequent clinical trials are then warranted to test whether such SPPARM effects could translate into clinical benefits.
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Acknowledgments |
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We thank Helga Bach, Susanne Betz, Renate Durst, and Miriam Grüb for excellent technical assistance.
Sources of Funding
This work was supported by grants of the Deutsche Forschungsgemeinschaft (SFB 451, project B9 and B11) to N.M. and D.W., a grant from the Landesforschungsschwerpunkt Baden-Württemberg to N.M., a grant from the Else-Kröner-Fresenius-Stiftung to D.W., and a grant of the Deutsche Diabetes Gesellschaft (Anschubförderung) to K.H. N.M. has received an unrestricted research grant from Boehringer-Ingelheim.
Disclosures
N.M. has received unrestricted research grants from Boehringer Ingelheim, Glaxo Smith Kline, and Takeda Pharma and has given lectures for Boehringer Ingelheim, Glaxo Smith Kline, and Takeda Pharma. U.K. has received unrestricted research grants from Boehringer Ingelheim and Glaxo Smith Kline and has given lectures for Boehringer Ingelheim, Glaxo Smith Kline, and Takeda Pharma. The remaining authors report no conflicts.
Received July 30, 2007; first decision August 14, 2007; accepted November 19, 2007.
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  K. Yamamoto, M. Ohishi, C. Ho, T. W. Kurtz, and H. Rakugi Telmisartan-Induced Inhibition of Vascular Cell Proliferation Beyond Angiotensin Receptor Blockade and Peroxisome Proliferator-Activated Receptor-{gamma} Activation Hypertension, December 1, 2009; 54(6): 1353 - 1359. [Abstract] [Full Text] [PDF]
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