title: Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse.
abstract: OBJECTIVE
  Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARalpha/gamma agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development.
  
  
  METHODS
  Six-week-old male apoE KO mice were randomised to receive the dual PPARalpha/gamma agonist, compound 3q (3 mg/kg/day), the PPARgamma agonist, rosiglitazone (20 mg/kg/day), the PPARalpha agonist, gemfibrozil (100 mg/kg/day) by gavage or no treatment for 20 weeks (n=12/group).
  
  
  RESULTS
  Gemfibrozil and rosiglitazone significantly reduced lesion area. However, compound 3q was associated with a three-fold increase in total plaque area (versus control p<0.001). This was associated with an upregulation of markers of plaque instability including vascular cell adhesion molecule-1 (3.5-fold, p<0.001), P-selectin (3.4-fold, p<0.001) monocyte chemoattractant protein-1 (3.4-fold; p<0.001) as well as the scavenger receptor, CD36 (2-fold, p<0.01). These disparate effects were observed with the dual PPAR agonist despite lowering LDL cholesterol and improving insulin sensitivity to a similar extent to PPARalpha and gamma agonists used individually.
  
  
  CONCLUSIONS
  The finding of increased atherogenesis following a dual PPARalpha/gamma agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches.
authors.affiliation: Danielle Alberti Memorial Centre for Diabetic Complications, Baker Medical Research Institute, Melbourne, Australia. anna.calkin@baker.edu.au
authors.forename: Anna C
authors.initials: AC
authors.lastname: Calkin
authors.forename: Terri J
authors.initials: TJ
authors.lastname: Allen
authors.forename: Markus
authors.initials: M
authors.lastname: Lassila
authors.forename: Christos
authors.initials: C
authors.lastname: Tikellis
authors.forename: Karin A
authors.initials: KA
authors.lastname: Jandeleit-Dahm
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics*; D001794:Blood Pressure; D002318:Cardiovascular Diseases / Q000235:genetics; D002448:Cell Adhesion; D015248:Gemfibrozil / Q000494:pharmacology; D020869:Gene Expression Profiling; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D008055:Lipids; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015248:Gemfibrozil