title: Early Changes in Cytochrome P450s and Their Associated Arachidonic Acid Metabolites Play a Crucial Role in the Initiation of Cardiac Hypertrophy Induced by Isoproterenol.
abstract: Cytochrome P450 enzymes (P450s), along with their cardioprotective metabolites the epoxyeicosatrienoic acids (EETs) and cardiotoxic metabolite 20-hydroxyeicosatetraeonic acid (20-HETE), were found to be altered in cardiac hypertrophy; however, it is unclear whether these changes are causal or epiphenomenon. Therefore, we hypothesized that P450s and their metabolites play a crucial role in the initiation of cardiac hypertrophy. To test our hypothesis, rats and RL-14 cells were treated with the hypertrophic agonist isoproterenol for different time periods. Thereafter, in vivo heart function and wall thickness were assessed using echocardiography. Moreover, the role of P450 epoxygenases, ω-hydroxylases, and soluble epoxide hydrolase (sEH) were determined at mRNA, protein, and activity levels using real-time polymerase chain reaction, Western blot, and liquid chromatography-mass spectrometry, respectively. Our results show that in vivo and in vitro hypertrophy was initiated after 72 hours and 6 hours of isoproterenol treatment, respectively. Studies performed at the prehypertrophy phase showed a significant decrease in P450 epoxygenases along with a significant induction of sEH activity. Consequently, lower EET and higher dihydroxyeicosatrienoic acid levels were observed during this phase. However, significant increases in P450 ω-hydroxylase along with its associated metabolite, 20-HETE, were detected only in vivo. Interestingly, increasing EET levels by P450 epoxygenase induction, sEH inhibition, or exogenous administration of EET prevented the initiation of cardiac hypertrophy through a nuclear factor-κB-mediated mechanism. Taken together, these findings reveal a crucial role of P450 epoxygenases and EETs in the development of cardiac hypertrophy, which could uncover novel targets for prevention of heart failure at early stages.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hassan N
authors.initials: HN
authors.lastname: Althurwi
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Zaid H
authors.initials: ZH
authors.lastname: Maayah
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Osama H
authors.initials: OH
authors.lastname: Elshenawy
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada aelkadi@ualberta.ca.
authors.forename: Ayman O S
authors.initials: AO
authors.lastname: El-Kadi
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology*; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D006334:Heart Function Tests; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D007545:Isoproterenol / Q000009:adverse effects*; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014463:Ultrasonography
chemical_list: D000319:Adrenergic beta-Antagonists; D001095:Arachidonic Acids; D006893:Hydroxyeicosatetraenoic Acids; D016328:NF-kappa B; D012333:RNA, Messenger; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D007545:Isoproterenol