Synthesis Of PPARα Agonist OEA And Study Of The Relationship Between OEA And Atherosclerosis

Atherosclerosis,the principal cause of heart attack,stroke and gangrene of the extremities,accounts for 50%of mortality in the USA,Europe and Japan,which threatens human health in 21 century.The American Heart Association estimates that cardiovascular diseases affect 60 million Americans.In China,incidence of cardiovascular diseases is rising by years and the age of patients show a trend of getting younger with the development of economy and aging of population.Scientists have put their focus on searching for new drug for atherosclerosis.Statins are wide-used drug for their visible effects on atherosclerosis,but they have little effect on rising of HDL-C,lowering of TG and improvement of insulin resistance.PPARαagonists show advantage on rising of HDL-C,lowering of TG and improvement of endothelial cell function,therefore finding new and more effective PPARαagonists has been the main research field of development of drug for atherosclerosis and metabolic syndrome.The purpose of our study is to demonstrate the activity of oleoyethanolamide to PPARs,and to investigate the effects of oleoyethanlamide on primary inflammatory markers in atherosclerosis,and to explain the effects of PPARs on atherosclerosis. Transactivation assay was used to determine the activity of oleoyethanolamide to PPARs;real-time PCR and western blotting were used to detect the mRNA and protein expression of PPARαin cultured HUVECs;real-time PCR,enzyme liked immunosorbent assay and immunocytochemistry were used to detect the mRNA and protein expression of adhesion molecules(vascular cellular adhesion molecule-1 and intercellular adhesion molecule-1) in TNF-αinduced HUVECs.The results of our study suggest that oleoyethanolamide activate PPARαand PPARβ,but the activity of oleoyethanolamide to PPARαis much bigger than to PPARβ.Therefore,oleoyathanolamide has high affinity to PPARαand is an effective agonist of PPARα.Contemporarily,oleoyethanolamide significantly inhibits the expression of adhesion molecules in TNF-αinduced HUVECs,and compared with fenofibrate,the clinically wide used PPARαagonist,the oleoyethanolamide is more effective to inhibit expression of adhesion molecules.Suggested mechanism is that PPARαis activated after binding with ligand,and then the activated PPARαcould physically sequester away the P65 subunit of NF-κB,results to repress the gene expression of adhesion molecules by preventing NF-κB specifically binding toκB site of adhesion molecules promotor.On the other hand,unliganded PPARβassociates with the repressor,BCL-6.Upon ligand activation,the repressor is released from PPARβ.The redistribution of BCL-6 inhibits the expression of P50 subunit of NF-κB and its precursor P105,which represses the gene expression of adhesion molecules also.Activation of PPARs can lead to inhibition of primary inflammatory markers in atherosclerosis.Oleoyethanolamide inhibits expression of adhesion molecules in TNF-αinduced HUVECs through a PPARs pathway.Our results indicate that oleoyethanolamide has effects in preventing and curing atherosclerosis.