Abstract 12249: Activation of Prostaglandin E Receptor 4 Ameliorates Perivascular Inflammation and Pulmonary Hypertension in Rats

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Introduction: Perivascular inflammation is involved in the progression of vascular remodeling and pulmonary arterial hypertension (PAH). Activation of prostaglandin E receptor 4 (EP 4 ) has recently been reported to reduce inflammation in ulcerative colitis and osteoarthritis, but there are no reports on perivascular inflammation in PAH. Hypothesis: EP 4 agonist ameliorate perivascular inflammation, vascular remodeling and pulmonary hypertension (PH). Methods and Results: We investigated the effects of EP 4 agonist (KAG-308) on hemodynamics and pulmonary artery remodeling in a monocrotaline (MCT)-exposed rat model of PH. Immunohistochemistry detected predominant expression of EP4 proteins in the macrophages and endothelial layer of pulmonary arteries in the lungs of normal and MCT-exposed rats. Compared to normal rats, MCT-exposed rats had increased nuclear factor kappa B (NFκB) activation and significantly higher interleukin 6 ( IL -6) mRNA levels (1.0±0.4 vs 62.3±39.7, p < 0.05) in the lungs, and showed elevated right ventricular systolic pressure (RVSP; 29.7±1.8 vs 81.0±18.5 mmHg, p < 0.0001), total pulmonary vascular resistance index (TPRI; 91.0±12.1 vs 161.4 ± 37.0 mmHg/mL/min/g, p < 0.001) and RV hypertrophy (0.32±0.02 vs 0.57±0.10, p < 0.0001), together with medial wall thickening and perivascular macrophage accumulation on day 21 after MCT injection. Oral administration of EP 4 agonist KAG-308 (1 mg/kg, twice daily, by gavage, day 0 to 21) significantly reduced NFκB activation and interleukin-6 mRNA levels (6.8 ± 2.5, p < 0.05) in the lungs. Furthermore, KAG-308 prevented the elevated RVSP (53.1 ± 9.3 mmHg, p < 0.01), TPRI (112.0 ± 16.6 mmHg/mL/min/g, p < 0.05) and RV hypertrophy (0.47 ± 0.04, p < 0.05) by inhibiting medical wall thickening and macrophage accumulation. Conclusion: EP 4 agonist ameliorated inflammation, vascular remodeling and PH in MCT-exposed rat. The EP 4 agonist KAG-308 is a potential therapeutic agent for the treatment of PAH.