Mechanism Of Cardiac Injury Induced By CYP2J Knockout And Inhibition

Cytochrome P450 2J(CYP2J)mainly expressed in heart not only metabolizes exogenous drugs but also mediates the biotransformation of endogenous substances.CYP2 J metabolizes arachidonic acid(AA)to eepoxyeicosatrienoic acids(EETs).EETs are important substances to protect cardiovascular system.Based on the CYP2j3/10 gene knockout(KO)rat model,this thesis explored the mechanism of the cardiac injury caused by CYP2 J knockout and inhibition.Firstly,we compared the changes of EETs in plasma of wild-type(WT)rats and Cyp2j3/10 KO rats,and explored the effects of CYP2 J knockout on cardiac physiological function and myocardial damage.Results showed that Cyp2j3/10 deficiency reduced 11,12-EET and 14,15-EET in rat plasma and disrupted mitochondrial function,leading to myocarditis,myocardial hyperplasia and fibrosis.However,the deletion of Cyp2j3/10 initiated cardiac self-protection by upregulating cardiac function gene Myh7,Dsp,Tnni3,Tnni2,Scn5 a.Interestingly,the protection disappeared with the age,and old KO rats showed more severe myocardial damage.Secondly,this thesis further explores the mechanism of cardiac injury caused by CYP2 J enzyme activity inhibition.The results showed that sorafenib as a strong inhibitor of CYP2 J significantly reduced the level of EETs in WT rats.The reduction of EETs further broke the balance between mitochondrial fusion and fission factors in heart,and down-regulated the expression of mitochondrial energy supply and structural factors Pgc-1β,Pgc-1α,Ampk,Sirt1 and cardiac function gene Scn5 a,Prkag2,thus increasing the risk of arrhythmia and heart failure.In conclusion,this thesis demonstrated that the deletion and inhibition of CYP2 J can both lead to a decrease of EETs content and cause cardiac damage.This study provides a reference for further research on the function of CYP2 J and its mediated cardiac side effects of drugs.