Unique mechanistic insights into the beneficial effects of soluble epoxide hydrolase inhibitors in the prevention of cardiac fibrosis

Abstract

Tissue fibrosis represents one of the largest groups of diseases for which there are very few effective therapies. In the heart, myocardial infarction (MI) resulting in the loss of cardiac myocytes can culminate in adverse cardiac remodeling leading to eventual heart failure. Adverse cardiac remodeling includes myocyte hypertrophy, fibrosis, and electrical remodeling. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase inhibitors (sEHIs) in different models of cardiac hypertrophy and failure. Here, we directly determine the molecular mechanisms underlying the beneficial effects of sEHIs in cardiac remodeling post-MI. Treatment with a potent sEHI, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea (TPPU), which was started 1 wk post-MI in a murine model, results in a significant improvement in cardiac function. Importantly, treatment with TPPU results in a decrease in cardiac fibrosis as quantified using histological and immunostaining techniques. Moreover, single-cell-based assays demonstrate that treatment with TPPU results in a significant decrease not only in the percentages but also the proliferative capacity of different populations of cardiac fibroblasts as well as a reduction in the migration of fibroblasts into the heart from the bone marrow. Our study provides evidence for a possible unique therapeutic strategy to reduce cardiac fibrosis and improve cardiac function post-MI.

Inhibition of soluble epoxide hydrolase prevents renal interstitial fibrosis and inflammation

“…The effect of sEH inhibition on renal protection independently of its effect on lowering blood pressure was previously reported in streptozotocin-induced diabetic mice (11) and in DOCA-salt hypertension (34). Our data are also consistent with a recent report demonstrating the beneficial effects of sEH inhibitors on adverse cardiac remodeling in ischemic cardiomyopathy and pressure-overload hypertrophy (42). On the other hand, in a recent report, pharmacological inhibition of sEH attenuated collagen deposition in angiotensin II-treated heart ventricles, but genetic inhibition of sEH conversely aggravated the effect (31) showing differing effects of pharmacological and genetic inhibition of sEH on myocardial fibrosis.…”

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

“…3-(1-propionylpiperidine-4-yl)urea (TPPU: a potent sEH inhibitor) (31)(32)(33) and the endogenous eicosanoid 14,15-EET on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. Both TPPU and 14,15-EET potentiated NGF-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner (Fig.…”

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

“…6), an IND candidate, into a marketed drug largely due to mediocre efficacy and short half-life. sEH inhibitors have also been investigated for the improvement of cardiac function and reduction of cardiac fibrosis after myocardial infarction in a mouse model (Sirish et al, 2013). Trials for cardiac hypertrophy caused by fibrosis are notoriously expensive and long; however, there is a serious need for drugs that will attenuate hypertrophy.…”