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(Circulation. 2004;109:2054-2057.)
© 2004 American Heart Association, Inc.
Brief Rapid Communications |
Activity
From the Center for Cardiovascular Research, Institut für Pharmakologie und Toxikologie, Campus Charité-Mitte, Charité-Universitätsmedizin Berlin (M.S., R.C., T.U., U.K.), and HELIOS Klinikum Berlin, Franz Volhard Klinik, Campus Berlin-Buch, Charité-Universitätsmedizin Berlin (J.J.), Berlin, Germany.
Correspondence to Ulrich Kintscher, MD, Center for Cardiovascular Research, Institut für Pharmakologie und Toxikologie, Campus Charité-Mitte, Charité-Universitätsmedizin Berlin, Hessische Strasse 3/4, 10115 Berlin, Germany. E-mail ulrich.kintscher{at}charite.de
Received August 4, 2003; de novo received November 14, 2003; revision received March 16, 2004; accepted March 19, 2004.
| Abstract |
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(PPAR
) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPAR
function by ARBs.
Methods and Results The ARBs irbesartan and telmisartan (10 µmol/L) potently enhanced PPAR
-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3±0.1-fold induction; telmisartan: 3.1±0.3-fold induction; both P<0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 µmol/L: 3.6±0.3-fold induction; P<0.01), whereas eprosartan up to 100 µmol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 µmol/L) markedly induced transcriptional activity of PPAR
by 3.4±0.9-fold and 2.6±0.6-fold (P<0.05), respectively, compared with 5.2±1.1-fold stimulation by the PPAR
ligand pioglitazone (10 µmol/L). Irbesartan and telmisartan also induced PPAR
activity in an AT1R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPAR
activity independent of their AT1R blocking actions.
Conclusions The present study demonstrates that a specific subset of ARBs induces PPAR
activity, thereby promoting PPAR
-dependent differentiation in adipocytes. The activation of PPAR
demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.
Key Words: diabetes mellitus insulin angiotensin pharmacology
| Introduction |
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|
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The nuclear hormone receptor peroxisome proliferatoractivated receptor-
(PPAR
) plays an important role in the regulation of insulin sensitivity.4 Activated by its ligands such as prostaglandins or synthetic insulin-sensitizing thiazolidinediones/glitazones, PPAR
functions as a transcriptional regulator of multiple genes involved in glucose and lipid metabolism, thereby ameliorating type 2 diabetes.4
To elucidate the underlying mechanisms of the antidiabetic effect of ARBs, we investigated the effects of different ARBs on PPAR
function in 3T3-L1 cells, an established cell model to study PPAR
function.
| Methods |
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Semiquantitative RT-PCR and Quantitative Real-Time PCR
Real-time polymerase chain reaction (PCR) was performed as previously described with an ABI 7000 sequence detection system for real-time PCR.6 Mouse 18S ribosomal RNA for real-time PCR and hypoxanthine guanine phosphoribosyl transferase or ß-actin for semiquantitative reverse transcription (RT)PCR were chosen as endogenous controls (housekeeping genes).
Transfection and Luciferase Assay
Transient transfection and luciferase assays were performed as previously described.7 3T3-L1 cells (day 4) and PC12W cells were transfected with the use of Lipofectamine 2000 (Invitrogen) with 1 µg (3T3-L1 cells) or 50 ng (PC12W cells) 3xAcyl-CoA oxidase PPAR response element (PPRE)TK-luciferase reporter construct; PPAR
2 (10 ng) and RXR
(10 ng) expression vectors, provided by Dennis Bruemmer and Ronald Law (University of California at Los Angeles)7; pGal4-hPPAR
DEF (hPPAR
ligand-binding domain [LBD] fused to Gal4 DBD) and pGal5-TK-pGL3, provided by Bart Staels (UR 545 INSERM, Institut Pasteur de Lille, Lille, France); and 10 ng pRL-CMV, a renilla luciferase control reporter vector. After 4 hours, transfection medium was replaced by 10% FBS DMEM plus the indicated ARBs, pioglitazone, or vehicle (dimethyl sulfoxide), and luciferase activity was measured after 24 hours.
Statistical Analysis
ANOVA and t test were performed for statistical analysis as appropriate. Statistical significance was designated at P<0.05. Values are expressed as mean±SD.
| Results |
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ligand pioglitazone stimulated aP2 expression by 4.5±1-fold (10 µmol/L; P<0.01) compared with Mix alone (Figure 1B).
|
The PPAR
antagonist GW9662 (30 µmol/L) significantly blocked aP2 expression induced by pioglitazone (1 µmol/L), telmisartan (10 µmol/L), and irbesartan (100 µmol/L) to comparable extents (Data Supplement Figure, A).
ARBs Induce PPAR
Activity
Treatment of PPRE-transfected 3T3-L1 cells with irbesartan and telmisartan (10 µmol/L) markedly induced transcriptional activity of PPAR
3.4±0.9-fold and 2.6±0.6-fold, respectively (both P<0.05 versus vehicle-treated cells), compared with 5.2±1.1-fold stimulation by pioglitazone at the same concentration (P<0.01 versus vehicle-treated cells) (Data Supplement Figure, B). Consistent with the effects on aP2 expression, losartan induced PPAR
-dependent transcription only at high concentrations (100 µmol/L: 2.2±0.46-fold; P<0.05 versus vehicle-treated cells), and eprosartan had no effect (Data Supplement Figure, B).
ARBs Activate the PPAR
LBD
To provide further insight into the mechanism whereby ARBs induce PPAR
activity, we assessed their ability to activate the chimeric Gal4-DBD-hPPAR
-LBD fusion protein on a Gal4-dependent luciferase reporter. In this system, the activation of the reporter is mediated solely through activation of the PPAR
LBD. Treatment with the ARBs led to a concentration-dependent activation of the reporter (losartan EC50: >50 µmol/L; irbesartan EC50: 26.97 µmol/L; telmisartan EC50: 5.02 µmol/L; pioglitazone EC50: 0.2 µmol/L) (Figure 2A).
|
Irbesartan and Telmisartan Induce PPAR
Activity Independent of the AT1R
To study the role of the AT1R blocking actions of ARBs during PPAR
activation, PPAR
2 and its heterodimeric partner RXR
were overexpressed in an AT1R-deficient cell model (PC12W cells) (Figure 2B, box), and PPAR
-dependent transcription was measured with and without ARBs and pioglitazone. No regulation of PPAR
activity was observed in the absence of exogenous PPAR
2/RXR
(Figure 2B). After overexpression of the PPAR
2/RXR
heterodimer, irbesartan and telmisartan also induced PPAR
activity in AT1R-deficient PC12W cells, clearly demonstrating that these compounds stimulate PPAR
activation independent of their AT1R blocking actions (irbesartan: 2.1±0.3-fold; telmisartan: 1.9±0.4-fold; both P<0.05 versus vehicle-treated cells; pioglitazone: 4.2±1.4-fold; P<0.01 versus vehicle-treated cells).
| Discussion |
|---|
|
|
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activity by interaction with the PPAR
-LBD, thereby promoting PPAR
-dependent differentiation in 3T3-L1 adipocytes. Activation of PPAR
by these ARBs was also observed in the absence of AT1Rs, demonstrating that the activation is independent of blocking the AT1R. The induction of PPAR
activity demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.
We identified ARBs with PPAR
-activating properties at low (telmisartan), medium (irbesartan), and very high concentrations (losartan) as well as a nonactivating ARB (eprosartan). Significant differences among the PPAR
-activating ARBs are likely caused by their physicochemical properties.8 High lipophilicity is required to obtain sufficiently high penetration rates to bind to intracellular PPAR
. Telmisartan, the ARB with the highest lipophilicity, most potently induced PPAR
-dependent aP2 expression and PPAR
2 LBD activation at pharmacologically relevant concentrations.8 These data imply that PPAR
-activating potency correlates with the degree of lipophilicity among the ARBs (telmisartan > irbesartan > losartan), whereas the maximal response may depend on other characteristics. When PPAR
-activating ARBs were compared with the PPAR
ligand pioglitazone, these compounds behaved like partial PPAR
agonists compared with the full agonism of glitazones. The detailed differences between PPAR
-activating ARBs and glitazones will be elucidated by understanding the molecular mechanism of PPAR
activation by lipophilic ARBs (eg, direct binding to the LBD, coactivator recruitment), which remains to be determined in the future.
ARBs that activate PPAR
have also been demonstrated to stimulate the expression of major PPAR
target genes in in vivo animal models. The improvement of insulin sensitivity in obese Zucker rats by irbesartan was associated with a marked upregulation of the PPAR
target gene glucose transporter-4 (GLUT-4).3,5 These data indicate that PPAR
activation by ARBs translates in the regulation of PPAR
target genes in vivo.
Despite the effects in animal models, clinical data in insulin-resistant or diabetic patients are still limited. Hypertensive patients receiving losartan had a 25% lower rate of new-onset diabetes than the atenolol-treated group, implicating an antidiabetic action of losartan.2 In our study losartan failed to induce PPAR
activity in pharmacologically relevant concentrations, suggesting additional antidiabetic mechanisms regulated by losartan or its active metabolites. Angiotensin II has been recently shown to inhibit intracellular insulin signaling, which was restored by AT1R antagonism.9 Beneficial effects of ARBs on impaired insulin signaling may represent an additional molecular mechanism for insulin sensitization by these compounds. Telmisartan stimulated PPAR
at pharmacologically relevant concentrations. The concentrations needed for PPAR
activation are achieved in the plasma of hypertensive patients treated with telmisartan (280 ng/mL=0.54 µmol/L), which will likely result in additional positive effects on insulin sensitivity in the dosages used for antihypertensive treatment.8 Beneficial effects of telmisartan not only on insulin sensitivity but also on plasma glucose lowering as well as an improved overall diabetic situation remain to be seen in suitable in vivo models and in clinical studies.
Angiotensin-converting enzyme (ACE) inhibitors have also been shown to prevent the onset of diabetes mellitus; however, the ACE inhibitor captopril was unable to induce PPAR
-mediated human adipocyte differentiation.6 ACE inhibitors improve insulin sensitivity via the bradykinin pathway, which demonstrates an alternative antidiabetic mechanisms of these compounds.10
In conclusion, PPAR
activation by a specific subset of ARBs may provide new therapeutic options in the treatment of patients with the metabolic syndrome. In addition, the pharmacological characteristics of PPAR
-activating ARBs may serve as a starting point for the development of future substances combining dual functions (AT1R antagonism and PPAR
activation) to treat hypertension and insulin resistance/type 2 diabetes.
| Acknowledgments |
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| Footnotes |
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Dr Unger is a member of the advisory boards for Boehringer Ingelheim, MSD, Abbott, Novartis, Glaxo-Smith-Kline, and Takeda.
| References |
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3. Henriksen EJ, Jacob S, Kinnick TR, et al. Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension. 2001; 38: 884890.
4. Picard F, Auwerx J. PPAR(gamma) and glucose homeostasis. Annu Rev Nutr. 2002; 22: 167197.[CrossRef][Medline] [Order article via Infotrieve]
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7. Kintscher U, Lyon C, Wakino S, et al. PPARalpha inhibits TGF-betainduced beta5 integrin transcription in vascular smooth muscle cells by interacting with Smad4. Circ Res. 2002; 91: e35e44.
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K. Sugimoto, N. R. Qi, L. Kazdova, M. Pravenec, T. Ogihara, and T. W. Kurtz Telmisartan But Not Valsartan Increases Caloric Expenditure and Protects Against Weight Gain and Hepatic Steatosis Hypertension, May 1, 2006; 47(5): 1003 - 1009. [Abstract] [Full Text] [PDF] |
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J.-a Kim, M. Montagnani, K. K. Koh, and M. J. Quon Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms Circulation, April 18, 2006; 113(15): 1888 - 1904. [Abstract] [Full Text] [PDF] |
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M. Schupp, L. D. Lee, N. Frost, S. Umbreen, B. Schmidt, T. Unger, and U. Kintscher Regulation of Peroxisome Proliferator-Activated Receptor {gamma} Activity by Losartan Metabolites Hypertension, March 1, 2006; 47(3): 586 - 589. [Abstract] [Full Text] [PDF] |
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K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, J.-a Kim, Y. Lee, and E. K. Shin Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients Diabetes Care, February 1, 2006; 29(2): 195 - 201. [Abstract] [Full Text] [PDF] |
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K. K. Koh, S. H. Han, and M. J. Quon Inflammatory Markers and the Metabolic Syndrome: Insights From Therapeutic Interventions J. Am. Coll. Cardiol., December 6, 2005; 46(11): 1978 - 1985. [Abstract] [Full Text] [PDF] |
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M. Schupp, M. Clemenz, R. Gineste, H. Witt, J. Janke, S. Helleboid, N. Hennuyer, P. Ruiz, T. Unger, B. Staels, et al. Molecular Characterization of New Selective Peroxisome Proliferator-Activated Receptor {gamma} Modulators With Angiotensin Receptor Blocking Activity Diabetes, December 1, 2005; 54(12): 3442 - 3452. [Abstract] [Full Text] [PDF] |
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J.-M. Vincent, Y. W. Kwan, S. Lung Chan, C. Perrin-Sarrado, J. Atkinson, and J.-M. Chillon Constrictor and Dilator Effects of Angiotensin II on Cerebral Arterioles Stroke, December 1, 2005; 36(12): 2691 - 2695. [Abstract] [Full Text] [PDF] |
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H. Zhang, A. Zhang, D.E. Kohan, R.D. Nelson, F.J. Gonzales, T. Yang, C. Schmidt-Lucke, L. Rossig, S. Fichtlscherer, M. Vasa, et al. Edema and Congestive Heart Failure from Thiazolidone Insulin Sensitizers--Excess Sodium Reabsoption in the Collecting Duct: Collecting Duct-Specific Deletion of Peroxisome Proliferator-Activated Receptor {gamma} Blocks Thiazolidinedione-Induced Fluid Retention. Proc Nat Acad Sci U S A 102: 9406-9411, 2005 J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3139 - 3142. [Full Text] [PDF] |
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T. Watanabe, J. Suzuki, H. Yamawaki, V. K. Sharma, S.-S. Sheu, and B. C. Berk Losartan Metabolite EXP3179 Activates Akt and Endothelial Nitric Oxide Synthase via Vascular Endothelial Growth Factor Receptor-2 in Endothelial Cells: Angiotensin II Type 1 Receptor-Independent Effects of EXP3179 Circulation, September 20, 2005; 112(12): 1798 - 1805. [Abstract] [Full Text] [PDF] |
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H. Abuissa, P. G. Jones, S. P. Marso, and J. H. O'Keefe Jr Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers for Prevention of Type 2 Diabetes: A Meta-Analysis of Randomized Clinical Trials J. Am. Coll. Cardiol., September 6, 2005; 46(5): 821 - 826. [Abstract] [Full Text] [PDF] |
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Z. T. Bloomgarden Second World Congress on the Insulin Resistance Syndrome: Hypertension, cardiovascular disease, and treatment approaches Diabetes Care, August 1, 2005; 28(8): 2073 - 2080. [Full Text] [PDF] |
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S. Yusuf, J. B. Ostergren, H. C. Gerstein, M. A. Pfeffer, K. Swedberg, C. B. Granger, B. Olofsson, J. Probstfield, J. V. McMurray, and on behalf of the Candesartan in Heart Failure--Ass Effects of Candesartan on the Development of a New Diagnosis of Diabetes Mellitus in Patients With Heart Failure Circulation, July 5, 2005; 112(1): 48 - 53. [Abstract] [Full Text] [PDF] |
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R. Clasen, M. Schupp, A. Foryst-Ludwig, C. Sprang, M. Clemenz, M. Krikov, C. Thone-Reineke, T. Unger, and U. Kintscher PPAR{gamma}-Activating Angiotensin Type-1 Receptor Blockers Induce Adiponectin Hypertension, July 1, 2005; 46(1): 137 - 143. [Abstract] [Full Text] [PDF] |
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M R Abdollahi, T R Gaunt, H E Syddall, C Cooper, D I W Phillips, S Ye, and I N M Day Angiotensin II type I receptor gene polymorphism: anthropometric and metabolic syndrome traits J. Med. Genet., May 1, 2005; 42(5): 396 - 401. [Abstract] [Full Text] [PDF] |
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J. L Reid Review: Molecular-specific effects of angiotensin II antagonists: clinical relevance to treating hypertension? Journal of Renin-Angiotensin-Aldosterone System, March 1, 2005; 6(1): 15 - 24. [Abstract] [PDF] |
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Y. Miura, N. Yamamoto, S. Tsunekawa, S. Taguchi, Y. Eguchi, N. Ozaki, and Y. Oiso Replacement of Valsartan and Candesartan by Telmisartan in Hypertensive Patients With Type 2 Diabetes: Metabolic and antiatherogenic consequences Diabetes Care, March 1, 2005; 28(3): 757 - 758. [Full Text] [PDF] |
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T. Lau, P.-O. Carlsson, P.S. Leung, C. Wolfrum, E. Asilmaz, E. Luca, J.M. Friedman, M. Stoffel, J.C. Verhave, H.L. Hillege, et al. Why Less Diabetes with Blockade of the Renin-Angiotensin System?: Evidence for a Local Angiotensin-Generating System and Dose-Dependent Inhibition of Glucose-Stimulated Insulin Release by Angiotensin II in Isolated Pancreatic Islets. Diabetologia 47: 240-248, 2004 J. Am. Soc. Nephrol., March 1, 2005; 16(3): 567 - 573. [Full Text] [PDF] |
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T. Watanabe, T. A. Barker, and B. C. Berk Angiotensin II and the Endothelium: Diverse Signals and Effects Hypertension, February 1, 2005; 45(2): 163 - 169. [Abstract] [Full Text] [PDF] |
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K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, Y.-H. Seo, M. H. Kang, T. H. Ahn, I. S. Choi, and E. K. Shin Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients Circulation, December 14, 2004; 110(24): 3687 - 3692. [Abstract] [Full Text] [PDF] |
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G. Nickenig Should Angiotensin II Receptor Blockers and Statins Be Combined? Circulation, August 24, 2004; 110(8): 1013 - 1020. [Full Text] [PDF] |
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