Soluble epoxide hydrolase inhibition exerts beneficial anti-remodeling actions post-myocardial infarction

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. Methods and 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 (Pb0.01; 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 (Pb < 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 (Pb<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 (Pb<0.05). GSK2188931B reduced macrophage infiltration into the PIZ (Pb<0.05). GSK2188931B reduced AngII-and TNF alpha-stimulated myocyte hypertrophy, AngII-and TGF beta-stimulated cardiac fibroblast collagen synthesis, including markers of gene expression ANP, beta-MHC, CTGF and CI (Pb<0.05). GSK2188931B reduced TNF alpha gene expression in lipopolysaccharide (LPS)stimulated monocytes (Pb<0.05). Conclusion: 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. (C) 2011 Elsevier Ireland Ltd. All rights reserved.