Circulation. 2004;109:2054-2057
Published online before print April 26, 2004, doi: 10.1161/01.CIR.0000127955.36250.65
Published online before print April 26, 2004, doi: 10.1161/01.CIR.0000127955.36250.65
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(Circulation. 2004;109:2054-2057.)
© 2004 American Heart Association, Inc.
Brief Rapid Communications |
Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-
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.
Background— Angiotensin type 1 receptor (AT1R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator–activated receptor-
(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
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