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  Molecular characterization of new selective peroxisome proliferator–activated receptor {gamma} modulators with angiotensin receptor blocking activity

Schupp, M., Clemenz, M., Gineste, R., Witt, H., Janke, J., Helleboid, S., et al. (2005). Molecular characterization of new selective peroxisome proliferator–activated receptor {gamma} modulators with angiotensin receptor blocking activity. Diabetes, 54, 3442-3452.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-8556-5 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-8557-3
Genre: Journal Article

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 Creators:
Schupp, Michael, Author
Clemenz, Markus, Author
Gineste, Romain, Author
Witt, Henning1, Author
Janke, Jürgen, Author
Helleboid, Stephane, Author
Hennuyer, Nathalie, Author
Ruiz, Patricia1, Author
Unger, Thomas, Author
Staels, Bart, Author
Kintscher, Ulrich, Author
Affiliations:
1Max Planck Society, ou_persistent13              

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Free keywords: ARB, angiotensin type 1 receptor blocker; AT1R, angiotensin type 1 receptor; FRET, fluorescence resonance energy transfer; GST, glutathione S-transferase; ITT, insulin tolerance test; LBD, ligand binding domain; NCoR, nuclear receptor corepressor; PPAR, peroxisome proliferator–activated receptor; PPRE, PPAR response element; RPE, R-phycoerythrin; SPPARM, selective PPAR modulators; TIF-2, transcriptional intermediary factor-2; TZD, thiazolidinedione
 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 PPAR{gamma}-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPAR{gamma} 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 PPAR{gamma} 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.

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Language(s): eng - English
 Dates: 2005-12
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: eDoc: 275505
 Degree: -

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Title: Diabetes
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 54 Sequence Number: - Start / End Page: 3442 - 3452 Identifier: ISSN: 0012-1797