Molecular Characterization of New Selective Peroxisome Proliferator–Activated Receptor γ Modulators With Angiotensin Receptor Blocking Activity

• Michael Schupp

  Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany

• Markus Clemenz

  Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany

• Romain Gineste

  GENFIT, Parc Eurasante, Loos, France

• Henning Witt

  Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany

• Jürgen Janke

  Franz Volhard Clinic, HELIOS Hospital Berlin, Charité Campus Buch, Charité-Universitätsmedizin Berlin, Berlin, Germany

• Stephane Helleboid

  GENFIT, Parc Eurasante, Loos, France

• Nathalie Hennuyer

  Department of Atherosclerose, Faculty of Pharmacy, Institute Pasteur Lille, University Lille II, UR 545 Institut National de la Santé et de la Recherche Médicale, Lille, France

• Patricia Ruiz

  Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany

• Thomas Unger

  Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany

• Bart Staels

  Department of Atherosclerose, Faculty of Pharmacy, Institute Pasteur Lille, University Lille II, UR 545 Institut National de la Santé et de la Recherche Médicale, Lille, France

• Ulrich Kintscher

  Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany

抄録

Selective peroxisome proliferator–activated receptor (PPAR) γ 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 PPARγ-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPARγ 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 PPARγ 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.

収録刊行物

• Diabetes

  Diabetes 54 (12), 3442-3452, 2005-12-01

  American Diabetes Association

キーワード

• Endocrinology, Diabetes and Metabolism
• Internal Medicine

詳細情報

• CRID: 1360574095048423424
• NII論文ID: 30026270172
• DOI: 10.2337/diabetes.54.12.3442
• ISSN: 1939327X
• ISSN: 00121797
• ISSN: http://id.crossref.org/issn/00121797
• Web Site: https://journals.org/diabetes/diabetes/article-pdf/54/12/3442/378710/zdb01205003442.pdf
• Web Site: https://diabetesjournals.org/diabetes/article-pdf/54/12/3442/378710/zdb01205003442.pdf
• データソース種別:
  • Crossref
  • CiNii Articles