Effects of pharmacological inhibition of the hydrolase activity of soluble epoxide hydrolase in a murine model of pulmonary hypertension associated or not with cardiac insufficiency

Abstract

We previously demonstrated that the inhibition of soluble epoxide hydrolase, which metabolizes vasodilator and anti-inflammatory eicosanoids, displays protective effects against left ventricular dysfunction in a rat model of ischemic heart failure. However, its remains to be investigated the impact of sEH inhibition on pulmonary vascular and right heart dysfunctions that are known to aggravate the prognostic of left heart diseases. To study the impact of sEH inhibition on pulmonary vascular and right heart dysfunctions in left heart diseases. Ischemic heart failure was induced by definitive coronary artery ligation in Sprague-Dawley rats. Pulmonary vascular function (Mulvany), edema (lung wet weight – dry weight), right ventricular function (cardiac MRI) and remodelling (right ventricular weight and fibrosis) were assessed in sham-operated rats and rats with HF treated or not by the sEH inhibitor TPPU (5 mg/L in drinking water) during 12 weeks. Rats with heart failure displayed a marked alteration in pulmonary smooth muscle constriction to norepinephrin and in pulmonary endothelial-dependent relaxation to acetylcholine, pulmonary edema, and an increase in right ventricular weight but not in fibrosis compared to sham-operated rats. TPPU did not modify these parameters in sham-operated rats but improved pulmonary relaxation to acetylcholine in rats with heart failure and reduced pulmonary edema without affecting right ventricular weight and fibrosis. Data obtained by cardiac MRI are currently being analysed. These preliminary results demonstrate that sEH inhibition improves pulmonary endothelial function in rats with heart failure, which could contribute to the beneficial effects of this new pharmacological class in the context of left heart diseases. This work was co-supported by European Union and Région Normandie. Europe gets involved in Normandie with European Regional Development Fund (ERDF).