title: Alterations in cytochrome P450-derived arachidonic acid metabolism during pressure overload-induced cardiac hypertrophy.
abstract: Cardiac hypertrophy is a major risk factor for many serious heart diseases. Recent data demonstrated the role of cytochrome P450 (CYP)-derived arachidonic acid (AA) metabolites in cardiovascular pathophysiology. In the current study our aim was to determine the aberrations in CYP-mediated AA metabolism in the heart during cardiac hypertrophy. Pressure overload cardiac hypertrophy was induced in Sprague Dawley rats using the descending aortic constriction procedure. Five weeks post-surgery, the cardiac levels of AA metabolites were determined in hypertrophied and normal hearts. In addition, the formation rate of AA metabolites, as well as, CYP expression in cardiac microsomal fraction was also determined. AA metabolites were measured by liquid chromatography-electrospray ionization-mass spectroscopy, whereas, the expression of CYPs was determined by Western blot analysis. Non-parametric analysis was performed to examine the association between metabolites formation and CYP expressions. Our results showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs), and 5-, 12-, 15-, and 20-hydroxyeicosatetraenoic acids (HETEs) levels were increased, whereas, 19-HETE formation was decreased in hypertrophied hearts. The increase in EETs was linked to CYP2B2. On the other hand, CYP1B1 and CYP2J3 were involved in mid-chain HETE metabolism, whereas, CYP4A2/3 inhibition was involved in the decrease in 19-HETE formation in hypertrophied hearts. In conclusion, CYP1B1 played cardiotoxic role, whereas, CYP2B2, CYP2J3 and CYP4A2/3 played cardioprotective roles during pressure overload-induced cardiac hypertrophy. These CYP can be valid targets for the development of drugs to treat and prevent cardiac hypertrophy and heart failure.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: El-Sherbeni
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2E1. Electronic address: aelkadi@ualberta.ca.
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System
keywords: Arachidonic acid metabolism; Cardiac hypertrophy; Cytochrome P450; Eicosanoids; Heart failure