Clin Res Cardiol 101, Suppl 1, April 2012

P377 - The balanced affinity dual PPAR-α/γ agonist aleglitazar up-regulates endothelial progenitor cells and reduces atherogenesis in mice
 
C. Gensch1, J. Pöss1, D. Lorenz1, V. Pavlickova1, C. Werner1, M. Böhm1, U. Laufs1
 
1Innere Medizin III, Kardiologie, Angiologie, intern. Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar;
 
The vascular effects of combined activation of the PPARα and the PPARγ receptor are not known. We therefore studied the effects of a novel dual PPARα/γ agonist, aleglitazar, on endothelial progenitor cells, endothelial function, angiogenesis and atherosclerosis in mice.
Methods and Results: Wildtype C57/Bl 6 mice were treated with aleglitazar, 10mg/kg/day i.p. or vehicle for 3 weeks. ApoE-/- mice were fed ad libidum with a western-type diet (21% fat, 19.5% casein, and 1.25% cholesterol) for 6 weeks and treated with aleglitazar (10 mg/kg/d i.p.) or vehicle. Body weight, blood pressure and heart rate were recorded weekly during the treatment and showed no significant differences between aleglitazar and vehicle treatments. As a proof of efficacy for the application of aleglitazar, serum adiponectin concentrations were determined by ELISA and showed a more than 5-fold up-regulation in both strains of mice. Serum parameters (lipids, glucose, electrolytes) measured at the beginning and twice during the treatment phase showed no significant differences between aleglitazar and vehicle in both strains.
To investigate the effects of dual PPARα/γ activation on EPC biology, Sca-1/VEGFR-2 positive EPC were quantified by FACS analysis. Treatment of wildtype mice with aleglitazar increased the number of circulating blood EPC to 153 ± 8.6 % and the number of bone marrow derived EPC to 197 ± 21 % of levels in vehicle treated mice. Spleen-derived cultured DiLDL/lectin double-positive EPC increased to 182 ± 8.4 %. SDF-1 induced migratory capacity of cultivated EPC was tested in a modified Boyden chamber assay. The treatment increased the migratory capacity of EPC to 176 ± 5.5 %. In vivo neoangiogenesis was measured using subcutaneously implanted discs and following systemic perfusion with fluorescent micropheres. Neoangiogenesis increased by two-fold after 20 days of aleglitazar treatment (204 ± 37.5 %, p <0.05).
To investigate the effects of aleglitazar on EPC in the context of dyslipidemia and endothelial dysfunction, ApoE-/- mice were fed a western-type diet and treated with aleglitazar (10 mg/kg/d ip.) for 6 weeks. In aleglitazar-treated mice, cultured DiLDL/lectin double-positive EPC increased to 256 ± 14 % of control. Treatment with aleglitazar increased the migratory capacity of EPC derived from ApoE-/- mice fed with western type diet to 149 ± 13.9 %.  Endothelium vasodilation was assessed in isolated aortic ring preparations of ApoE-/- mice fed with western-type diet for 6 weeks and treated with aleglitazar (10 mg/kg/d ip.) for 6 weeks or vehicle. Treatment with aleglitazar significantly improved endothelium dependent vasodilation in ApoE−/− mice compared to vehicle. Atherosclerosis was quantified by histomorphometric analyses of atherosclerotic lesions in the aortic sinus. Aleglitazar treatment reduced atherosclerotic plaque area compared to ApoE-/- control mice to 22.8 ± 7.8%. All results were statistically significant with n >5 per group and p< 0.05.
Conclusions: The study shows that combined PPARα and PPARγ agonism improves endothelial function, endothelial progenitor cells and atherogenesis in mice. The effects are independent of glucose lowering. Based on these data, clinical studies are warranted to test the effects of aleglitazar on vascular biology in humans.
 
Clin Res Cardiol 101, Suppl 1, April 2012
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-012-1100-6

http://www.abstractserver.de/dgk2012/ft/abstracts/P377.htm