title: Molecular characterization of new selective peroxisome proliferator-activated receptor gamma modulators with angiotensin receptor blocking activity.
abstract: Selective peroxisome proliferator-activated receptor (PPAR) gamma modulation is a new pharmacological approach that, based on selective receptor-cofactor interactions and target gene regulation, should result in potent insulin sensitization in the absence of PPARgamma-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPARgamma protein conformation using protease protection showed that telmisartan directly interacts with the receptor, producing a distinct conformational change compared with a glitazone. Glutathione S-transferase pull-down and fluorescence resonance energy transfer assays revealed selective cofactor binding by the ARBs compared with glitazones with an attenuated release of the nuclear receptor corepressor and absence of transcriptional intermediary factor 2 recruitment by ARBs. Consistently, selective cofactor binding resulted in differential gene expression profiles in adipocytes (ARB versus glitazone treated) assessed by oligo microarray analysis. Finally, telmisartan improved insulin sensitivity in diet-induced obese mice in the absence of weight gain. The present study identifies two ARBs as new SPPARMs. SPPARM activity by ARBs could retain the metabolic efficacy of PPARgamma activation with reduction in adverse effects exerting in parallel AT1 receptor blockade. This may provide a new therapeutic option for better cardiovascular risk management in metabolic diseases and may initiate the development of new classes of drugs combining potent antihypertensive and antidiabetic actions.
authors.affiliation: Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte Charité-Universitätsmedizin Berlin, Hessische Str., 3-4 10115 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
authors.forename: Markus
authors.initials: M
authors.lastname: Clemenz
authors.forename: Romain
authors.initials: R
authors.lastname: Gineste
authors.forename: Henning
authors.initials: H
authors.lastname: Witt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Janke
authors.forename: Stephane
authors.initials: S
authors.lastname: Helleboid
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hennuyer
authors.forename: Patricia
authors.initials: P
authors.lastname: Ruiz
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
mesh_terms: D016475:3T3 Cells; D000179:Acrylates / Q000494:pharmacology; D017667:Adipocytes; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D019556:COS Cells; D002454:Cell Differentiation; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D000077405:Irbesartan; D051379:Mice; D047495:PPAR gamma / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000077205:Pioglitazone; D011487:Protein Conformation; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000179:Acrylates; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D007093:Imidazoles; D047495:PPAR gamma; D013777:Tetrazoles; D045162:Thiazolidinediones; D013876:Thiophenes; C068373:eprosartan; D000077405:Irbesartan; D000077333:Telmisartan; D000077205:Pioglitazone