Rosiglitazone but not losartan prevents Nrf-2 dependent CD36 gene expression up-regulation in an in vivo atherosclerosis model.
BACKGROUND
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 PPARgamma activity.


METHODS
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.


RESULTS
HFHC was associated with increased PPARgamma gene expression without an over regulation of PPARgamma responsive genes, whereas RG and LST treatments were found to maintain PPARgamma activity without resulting in increased PPARgamma gene expression. A better anti-inflammatory and antioxidant profile in mice treated with RG regarding LST was observed in spite of a similar PPARgamma 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.


CONCLUSIONS
The PPARgamma 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 PPARgamma activity, our data suggests that these RG antioxidant effects are partially independent of its PPARgamma metabolizing properties.
Hernandez-Trujillo
Y
Y
Research Unit, Hospital Universitario de Gran Canaria Dr, Negrín, Las Palmas de Gran Canaria, Spain. yaridehernandez@hotmail.com
Rodriguez-Esparragon
F
F
Macias-Reyes
A
A
Caballero-Hidalgo
A
A
Rodriguez-Perez
Jose C
JC
D000818:Animals; D043303:Aryldialkylphosphatase / Q000097:blood; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics*; D018955:CD36 Antigens / Q000235:genetics*; D002265:Carboxylic Ester Hydrolases / Q000097:blood; D002791:Cholesterol, Dietary; D005786:Gene Expression Regulation; D015227:Lipid Peroxidation; D008054:Lipid Peroxides / Q000097:blood; D008055:Lipids / Q000097:blood; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D015854:Up-Regulation
D018955:CD36 Antigens; D002791:Cholesterol, Dietary; D008054:Lipid Peroxides; D008055:Lipids; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; D043303:Aryldialkylphosphatase; D019808:Losartan