20 Aug Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor- Activity
Michael Schupp, BPharm; Jürgen Janke, PhD; Ronald Clasen, BPharm; Thomas Unger, MD; Ulrich Kintscher, MD
Background: Αngiotensin 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 _mol/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 _mol/L: 3.6_0.3-fold induction; P_0.01), whereas eprosartan up to 100 _mol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 _mol/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 _mol/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. (Circulation. 2004;109: 2054-2057.)
Key Words: diabetes mellitus _ insulin _ angiotensin _ pharmacology