Restoration of Endothelial Function inPparα−/−Mice by Tempol

Abstract

Peroxisome proliferator activated receptor alpha (PPARα) is one of the PPAR isoforms belonging to the nuclear hormone receptor superfamily that regulates genes involved in lipid and lipoprotein metabolism. PPARαis present in the vascular wall and is thought to be involved in protection against vascular disease. To determine if PPARαcontributes to endothelial function, conduit and cerebral resistance arteries were studied inPparα−/−mice using isometric and isobaric tension myography, respectively. Aortic contractions to PGF2αand constriction of middle cerebral arteries to phenylephrine were not different between wild type (WT) andPparα−/−; however, relaxation/dilation to acetylcholine (ACh) was impaired. There was no difference in relaxation between WT andPparα−/−aorta to treatment with a nitric oxide (NO) surrogate indicating impairment in endothelial function. Endothelial NO levels as well as NO synthase expression were reduced inPparα−/−aortas, while superoxide levels were elevated. Two-week feeding with the reactive oxygen species (ROS) scavenger, tempol, normalized ROS levels and rescued the impaired endothelium-mediated relaxation inPparα−/−mice. These results suggest thatPparα−/−mice have impaired endothelial function caused by decreased NO bioavailability. Therefore, activation of PPARαreceptors may be a therapeutic target for maintaining endothelial function and protection against cardiovascular disease.