title: Soluble epoxide hydrolase inhibition exerts beneficial anti-remodeling actions post-myocardial infarction.
abstract: BACKGROUND
  A contributory role for soluble epoxide hydrolase (sEH) in cardiac remodeling post-myocardial infarction (MI) has been suggested; however effects of sEH inhibition following MI have not been evaluated. In this study, we examined in vivo post-MI anti-remodeling effects of a novel sEH inhibitor (GSK2188931B) in the rat, and evaluated its direct in vitro effects on hypertrophy, fibrosis and inflammation.
  
  
  RESULTS
  Post-MI administered GSK2188931B (80 mg/kg/d in chow) for 5 weeks improved left ventricular (LV) ejection fraction compared to vehicle-treated (Veh) rats (P<0.01; Sham 65 ± 2%, MI+Veh 30 ± 2%, MI+GSK 43 ± 2%) without affecting systolic blood pressure. Percentage area of LV tissue sections stained positive for picrosirius red (PS) and collagen I (CI) were elevated in LV non-infarct zone (P<0.05; NIZ; PS: Sham 1.46 ± 0.13%, MI+Veh 2.14 ± 0.22%, MI+GSK 1.28 ± 0.14%; CI: Sham 2.57 ± 0.17%, MI+Veh 5.06 ± 0.58%, MI+GSK 2.97 ± 0.34%) and peri-infarct zone (P<0.001; PIZ; PS: Sham 1.46 ± 0.13%, MI+Veh 9.06 ± 0.48%, MI+GSK 6.31 ± 0.63%; CI: Sham 2.57±0.17%, MI+Veh 10.51 ± 0.64%, MI+GSK 7.77 ± 0.57%); GSK2188931B attenuated this increase (P<0.05). GSK2188931B reduced macrophage infiltration into the PIZ (P<0.05). GSK2188931B reduced AngII- and TNFα-stimulated myocyte hypertrophy, AngII- and TGFβ-stimulated cardiac fibroblast collagen synthesis, including markers of gene expression ANP, β-MHC, CTGF and CI (P<0.05). GSK2188931B reduced TNFα gene expression in lipopolysaccharide (LPS)-stimulated monocytes (P<0.05).
  
  
  CONCLUSIONS
  sEH inhibition exerts beneficial effects on cardiac function and ventricular remodeling post-MI, and direct effects on fibrosis and hypertrophy in cardiac cells. These findings suggest that sEH is an important contributor to the pathological remodeling following MI, and may be a useful target for therapeutic blockade in this setting.
authors.affiliation: Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology & Preventive Medicine, Monash University, Alfred Hospital, Victoria, Australia. andrew.kompa@monash.edu
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Kompa
authors.forename: Bing H
authors.initials: BH
authors.lastname: Wang
authors.forename: Guoying
authors.initials: G
authors.lastname: Xu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Ho
authors.forename: Stephen
authors.initials: S
authors.lastname: Eisennagel
authors.forename: Reema K
authors.initials: RK
authors.lastname: Thalji
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D010880:Piperidines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014227:Triazines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: C584200:N-((4-bromo-2-((trifluoromethyl)oxy)phenyl)methyl)-1-(4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)-4-piperidinecarboxamide; D010880:Piperidines; D014227:Triazines; D004851:Epoxide Hydrolases