Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse.
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.
Calkin
Anna C
AC
Danielle Alberti Memorial Centre for Diabetic Complications, Baker Medical Research Institute, Melbourne, Australia. anna.calkin@baker.edu.au
Allen
Terri J
TJ
Lassila
Markus
M
Tikellis
Christos
C
Jandeleit-Dahm
Karin A
KA
Thomas
Merlin C
MC
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
D001057:Apolipoproteins E; D008055:Lipids; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D015248:Gemfibrozil