title: Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice.
abstract: OBJECTIVE
  The transcription factors, peroxisome proliferator-activated receptors (PPAR) alpha (alpha) and gamma (gamma), which are involved in lipid and glucose homeostasis, also exert modulatory actions on vascular cells where they exhibit anti-inflammatory and anti-proliferative properties. Hence, PPAR agonists potentially can affect atherogenesis both via metabolic effects and direct effects on the vessel wall. We tested whether the dual PPAR-alpha/gamma agonist, tesaglitazar (TZ), would reduce atherosclerosis in a non-diabetic, atherosclerosis-prone mouse model, independent of effects on plasma lipids.
  
  
  RESULTS
  Low-density lipoprotein receptor deficient (LDLr-/-) mice were fed a Western type diet consisting of 21% butterfat and 0.15% cholesterol, with or without TZ 0.5 micromol/kg of diet, for 12 weeks. TZ reduced atherosclerosis in the female, but not male, LDLr-/- mice without affecting cholesterol and triglyceride levels, HDL binding to biglycan, or the inflammatory markers serum amyloid A (SAA) and serum amyloid P (SAP). TZ also decreased adiposity in both genders.
  
  
  CONCLUSIONS
  TZ reduced atherosclerosis in the female LDLr-/- mice via lipid-independent mechanisms, probably at least in part by direct actions on the vessels. The body weight changes in these mice are different from the effects of dual PPAR agonists seen in humans.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: Ebele C
authors.initials: EC
authors.lastname: Chira
authors.forename: Timothy S
authors.initials: TS
authors.lastname: McMillen
authors.forename: Shari
authors.initials: S
authors.lastname: Wang
authors.forename: Antonio
authors.initials: A
authors.lastname: Haw
authors.forename: Kevin D
authors.initials: KD
authors.lastname: O'Brien
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
mesh_terms: D000476:Alkanesulfonates / Q000494:pharmacology*; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology*; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry; D005260:Female; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015233:Models, Statistical; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000494:pharmacology*; D011973:Receptors, LDL / Q000235:genetics* / Q000502:physiology
chemical_list: D000476:Alkanesulfonates; D001786:Blood Glucose; D008055:Lipids; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D011973:Receptors, LDL; C501413:tesaglitazar; D002784:Cholesterol