title: Regulation of peroxisome proliferator-activated receptor gamma activity by losartan metabolites.
abstract: Two active metabolites of the angiotensin type 1 (AT1) receptor blocker losartan have been described previously, EXP3174 and EXP3179. Whereas EXP3174 is the main antihypertensive AT1 receptor-blocking metabolite, the role of EXP3179 is widely unknown. Recently, a subgroup of AT1 receptor blockers has been identified as ligands for the peroxisome proliferator-activated receptor gamma (PPAR-gamma). Here we characterize the PPAR-gamma-activating properties of the 2 active losartan metabolites. PPAR-gamma activity was measured with a chimeric Gal4-DNA-binding domain-hPPARgamma-ligand-binding domain (LBD) fusion protein on a Gal4-dependent luciferase reporter system. EXP3179 prominently induced the activation of the PPAR-gamma-LBD reaching a maximum at 100 micromol/L with a 7.1+/-1-fold induction (P<0.05 versus vehicle-treated cells). Maximum PPAR-gamma-LBD activation by EXP3179 reached 51% of the maximum response induced by the full PPAR-gamma agonist pioglitazone, identifying EXP3179 as a partial PPAR-gamma agonist. EXP3174 did not induce PPAR-gamma-LBD activation. EC50 values were calculated for PPAR-gamma-LBD activity (pioglitazone EC50: 0.88 micromol/L; EXP3179 EC50: 17.1 micromol/L; losartan EC50: >50 micromol/L). Consistent with the activation of PPAR-gamma, EXP3179 potently induced 3T3-L1 adipocyte differentiation, a typical PPAR-gamma-dependent cell function, and markedly stimulated PPAR-gamma target gene expression. EXP3174 failed to regulate differentiation or PPAR-gamma target gene expression. The present study characterizes the active losartan metabolite EXP3179 as a partial PPAR-gamma agonist. PPAR-gamma activation by EXP3179 may help us to understand the beneficial metabolic effects of losartan observed in clinical trials.
authors.affiliation: Center for Cardiovascular Research, Institute of Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schupp
authors.forename: Lucas D
authors.initials: LD
authors.lastname: Lee
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Frost
authors.forename: Sumaira
authors.initials: S
authors.lastname: Umbreen
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
authors.forename: Thomas
authors.initials: T
authors.lastname: Unger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002522:Chlorocebus aethiops; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D019808:Losartan / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D008024:Ligands; D047495:PPAR gamma; D012333:RNA, Messenger; D013777:Tetrazoles; C073600:2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl)-1H-imidazole-5-carboxaldehyde; C066026:losartan carboxylic acid; D019808:Losartan