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(This work was supported by grants 81500287 from National Nature Science Foundation Committee of China)
The soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs) to their less active dihydroxy derivatives, dihydroxy epoxyeicosatrienoic acids (DHETs). The purpose of the study was to observe the effect of cis-4-[4-(3adamantan-1-yl-ureido) cyclohexyl-oxy]benzoic acid (c-AUCB), a sEH inhibitor, on hypoxia-induced pulmonary hypertension in rats.
Thirty-two male Sprague-Dawley rats (8 wk old) were randomized to normoxic (21% O2) or hypobaric hypoxia (10% O2) and treated with and without c-AUCB at 15 mg/kg body weight every day for 3 weeks (n=8 animals/treatment group). At the end of 3 wk, the rats were anesthetized and catheterized, and hemodynamic indices were measured, right ventricular hypertrophy index (RVHI, the weight ratio of right ventricle to the left ventricle plus septum) were calculated and vascular remodeling phenotypes were analyzed. The levels of transforming growth factor-β1 (TGF-β1) and interleukin-6 (IL-6) in the sera and the lung extracts were measured by enzyme-linked immunosorbent assay (ELISA). All CYP-dependently formed EETs and DHETs as determined by liquid chromatography/mass spectrometry.
The plasma ratio of EETs to DHETs was obviously increased in the c-AUCB treated groups compared with that in control group. Right ventricular systolic pressure (RVSP) and RVHI in the hypoxia group were significantly elevated compared with those in the normoxic group (59.7±6.4 vs 28.5± 3.1 mmHg, P<0.01; 0.47±0.03 vs 0.25±0.02, P<0.01). Treatment with c-AUCB significantly inhibited the elevation of RVSP (43.5±4.6 mmHg, P<0.01) and RVHI (0.33 ± 0.02, P<0.01) in the hypoxia rats. A significant increase occurred in percentage of medial-wall thickness in pulmonary arteries with an external diameter of 50–100 mm in the hypoxia group, whereas treatment with c-AUCB caused a marked reduction in the hypoxia rats but not in the normoxic rats. The concentrations of TGF-β1 and IL-6 in the sera and the lung extracts were both significantly increased in hypoxia-treated rats compared with normoxic-treated animals. Treatment with c-AUCB obviously inhibited the elevation of TGF-β1 and IL-6 in both the sera and the lung extracts (P<0.01).
Our findings suggested that soluble epoxide hydrolase inhibition attenuated pulmonary vascular remodeling and the development of pulmonary hypertension, partly by its anti-inflammatory property, in hypoxia-induced pulmonary hypertension in rats.