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. CONCLUSION: 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.
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-thiazolidinedionePPARalpha/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. CONCLUSION: 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: J W A van der Hoorn; J W Jukema; L M Havekes; E Lundholm; G Camejo; P C N Rensen; H M G Princen Journal: Br J Pharmacol Date: 2009-02-13 Impact factor: 8.739
Authors: Carlos Zaragoza; Carmen Gomez-Guerrero; Jose Luis Martin-Ventura; Luis Blanco-Colio; Begoña Lavin; Beñat Mallavia; Carlos Tarin; Sebastian Mas; Alberto Ortiz; Jesus Egido Journal: J Biomed Biotechnol Date: 2011-02-16