Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology & Preventive Medicine, Monash University, Alfred Hospital, Victoria, Australia.
Int J Cardiol. 2013 Jul 15;167(1):210-9. doi: 10.1016/j.ijcard.2011.12.062. Epub 2012 Jan 10.
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.
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).
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.
可溶性环氧化物水解酶（sEH）在心肌梗死后心脏重构中起作用；然而，心肌梗死后抑制 sEH 的作用尚未得到评估。在这项研究中，我们在大鼠体内研究了新型 sEH 抑制剂（GSK2188931B）在心肌梗死后的抗重构作用，并评估了其对肥大、纤维化和炎症的直接体外作用。
心肌梗死后给予 GSK2188931B（80mg/kg/d 饲料）5 周，与 vehicle 治疗（Veh）大鼠相比，左心室（LV）射血分数改善（P<0.01；Sham 65±2%，MI+Veh 30±2%，MI+GSK 43±2%），而不影响收缩压。LV 非梗死区（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%）和梗死周边区（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%）的 LV 组织切片中 picrosirius 红（PS）和胶原 I（CI）染色阳性面积增加（P<0.05）；GSK2188931B 减弱了这种增加（P<0.05）。GSK2188931B 减少了 PIZ 中的巨噬细胞浸润（P<0.05）。GSK2188931B 减少了 AngII 和 TNFα 刺激的心肌细胞肥大、AngII 和 TGFβ 刺激的心脏成纤维细胞胶原合成，包括基因表达标志物 ANP、β-MHC、CTGF 和 CI（P<0.05）。GSK2188931B 减少了脂多糖（LPS）刺激的单核细胞中 TNFα 的基因表达（P<0.05）。
sEH 抑制对心肌梗死后的心脏功能和心室重构有有益作用，并对心脏细胞的纤维化和肥大有直接作用。这些发现表明 sEH 是心肌梗死后病理性重构的重要贡献者，可能是该治疗靶点的有用抑制剂。
