title: Role of cytochrome P450-mediated arachidonic acid metabolites in the pathogenesis of cardiac hypertrophy.
abstract: A plethora of studies have demonstrated the expression of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) enzymes in the heart and other cardiovascular tissues. In addition, the expression of these enzymes is altered during several cardiovascular diseases (CVDs), including cardiac hypertrophy (CH). The alteration in CYP and sEH expression results in derailed CYP-mediated arachidonic acid (AA) metabolism. In animal models of CH, it has been reported that there is an increase in 20-hydroxyeicosatetraenoic acid (20-HETE) and a decrease in epoxyeicosatrienoic acids (EETs). Further, inhibiting 20-HETE production by CYP ω-hydroxylase inhibitors and increasing EET stability by sEH inhibitors have been proven to protect against CH as well as other CVDs. Therefore, CYP-mediated AA metabolites 20-HETE and EETs are potential key players in the pathogenesis of CH. Some studies have investigated the molecular mechanisms by which these metabolites mediate their effects on cardiomyocytes and vasculature leading to pathological CH. Activation of several intracellular signaling cascades, such as nuclear factor of activated T cells, nuclear factor kappa B, mitogen-activated protein kinases, Rho-kinases, Gp130/signal transducer and activator of transcription, extracellular matrix degradation, apoptotic cascades, inflammatory cytokines, and oxidative stress, has been linked to the pathogenesis of CH. In this review, we discuss how 20-HETE and EETs can affect these signaling pathways to result in, or protect from, CH, respectively. However, further understanding of these metabolites and their effects on intracellular cascades will be required to assess their potential translation to therapeutic approaches for the prevention and/or treatment of CH and heart failure.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Center for Pharmacy and Health Research, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Abdulaziz M S
authors.initials: AM
authors.lastname: Alsaad
authors.forename: Beshay N M
authors.initials: BN
authors.lastname: Zordoky
authors.forename: Mandy M Y
authors.initials: MM
authors.lastname: Tse
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 / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D016718:Arachidonic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System