Thiazolidinediones exert anti-inflammatory and anti-oxidative roles and attenuate atherosclerosis by mechanisms partially independent of their metabolizing actions. High doses of angiotensin type 1 receptor (AT1R) blocker losartan (LST) seem to promote fat cell formation by preserving PPAR├Ä┼é activity.
C57BL/6J diet-induced atherosclerotic susceptible mice randomly received a normal or a high-fat high-cholesterol (HFHC) diet and were treated with rosiglitazone (RG), LST or a vehicle for 12 weeks.
HFHC was associated with increased PPAR├Ä┼é gene expression without an over regulation of PPAR├Ä┼é responsive genes, whereas RG and LST treatments were found to maintain PPAR├Ä┼é activity without resulting in increased PPAR├Ä┼é gene expression. A better anti-inflammatory and antioxidant profile in mice treated with RG regarding LST was observed in spite of a similar PPAR├Ä┼é preserved activity. Chromatin immunoprecipitation (ChIP) assays revealed that animals under HFHC diet treated with RG showed a significant nuclear factor erythroid 2-like 2 (Nrf2)-dependent down-regulation of the expression of the CD36 gene.
The PPAR├Ä┼é agonist RG exerts antioxidant properties that significantly reduced Nrf-2-dependent CD-36 up-regulation in mice under HFHC diet. Because LST treatment was also associated with a preserved PPAR├Ä┼é activity, our data suggests that these RG antioxidant effects are partially independent of its PPAR├Ä┼é metabolizing properties.
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