title: Soluble epoxide hydrolase inhibition does not prevent cardiac remodeling and dysfunction after aortic constriction in rats and mice.
abstract: Epoxyeicosatrienoic acids, substrates for soluble epoxide hydrolase (sEH), exhibit vasodilatory and antihypertrophic activities. Inhibitors of sEH might therefore hold promise as heart failure therapeutics. We examined the ability of sEH inhibitors GSK2188931 and GSK2256294 to modulate cardiac hypertrophy, fibrosis, and function after transverse aortic constriction (TAC) in rats and mice. GSK2188931 administration was initiated in rats 1 day before TAC, whereas GSK2256294 treatment was initiated in mice 2 weeks after TAC. Four weeks later, cardiovascular function was assessed, plasma was collected for drug and sEH biomarker concentrations, and left ventricle was isolated for messenger RNA and histological analyses. In rats, although GSK2188931 prevented TAC-mediated increases in certain genes associated with hypertrophy and fibrosis (α-skeletal actin and connective tissue growth factor), the compound failed to attenuate TAC-induced increases in left ventricle mass, posterior wall thickness, end-diastolic volume and pressure, and perivascular fibrosis. Similarly, in mice, GSK2256294 did not reverse cardiac remodeling or systolic dysfunction induced by TAC. Both compounds increased the sEH substrate/product (leukotoxin/leukotoxin diol) ratio, indicating sEH inhibition. In summary, sEH inhibition does not prevent cardiac remodeling or dysfunction after TAC. Thus, targeting sEH seems to be insufficient for reducing pressure overload hypertrophy.
authors.affiliation: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Morgan
authors.forename: Alan R
authors.initials: AR
authors.lastname: Olzinski
authors.forename: John J
authors.initials: JJ
authors.lastname: Upson
authors.forename: Shufang
authors.initials: S
authors.lastname: Zhao
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Eisennagel
authors.forename: Bao
authors.initials: B
authors.lastname: Hoang
authors.forename: James R
authors.initials: JR
authors.lastname: Tunstead
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
authors.forename: Beat M
authors.initials: BM
authors.lastname: Jucker
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology; D003251:Constriction, Pathologic; D003514:Cyclohexylamines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005355:Fibrosis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014227:Triazines / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D003514:Cyclohexylamines; D004791:Enzyme Inhibitors; C584200:N-((4-bromo-2-((trifluoromethyl)oxy)phenyl)methyl)-1-(4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)-4-piperidinecarboxamide; C584201:N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide; D010880:Piperidines; D014227:Triazines; D004851:Epoxide Hydrolases