Abstract 4135357: Activation of prostaglandin E receptor 4 attenuates pulmonary vascular remodeling and pulmonary hypertension in monocrotaline-exposed rats via non-inflammatory pathway

Backgrounds: The prostacyclin pathway plays a pivotal role in the treatment of pulmonary arterial hypertension (PAH). Meanwhile, there is evidence that the expression of IP, the target of prostacyclin, is scant in PAH patients, whereas the prostaglandin E receptor 4 (EP 4 ) remains stable. EP 4 , similar to IP, exerts vasodilative effect via cAMP. In addition, an orally administrable selective EP 4 agonist, KAG-308, has shown to exert anti-inflammatory effect in patients with ulcerative colitis and the mouse with surgically induced osteoarthritis. However, the effect of KAG-308 on pulmonary vasculature of PAH remains unknown. Hypothesis: EP4 agonist ameliorates pulmonary vascular remodeling and pulmonary hypertension (PH). Methods and Results: We investigated the effects of KAG-308 on hemodynamics and pulmonary vascular remodeling in a monocrotaline (MCT)-exposed rat model of PH. Compared to normal rats, MCT-exposed rats had higher right ventricular systolic pressure (RVSP), total pulmonary vascular resistance index (TPRI) and RV hypertrophy, together with medial wall thickening and increased activation of nuclear factor kappa B (NFkB) and inflammatory cytokines in the lungs on day 21 after MCT injection. Chronic oral administration of KAG-308 (1 mg/kg, twice daily, by gavage, day 0 to 21) lowered RVSP (53.1 ± 9.3 vs 81.0±18.5 mmHg, p <0.01), TPRI (112.0 ± 16.6 vs 161.4 ± 37.0 mmHg/mL/min/g, p <0.05) and RV hypertrophy (0.47 ± 0.04 vs 0.57±0.10, p <0.05). Elastica van Gieson staining showed attenuation of medical wall thickening. Furthermore, KAG-308 significantly reduced NFkB activation and inflammatory cytokines such as Il6 , Mcp1 and Il1b in the lungs. In addition, chronic KAG-308 administration didn’t alter the level of cAMP in the lung, suggesting that the reduction of TPRI wasn’t the results of vasodilation. Interestingly, in human pulmonary artery smooth muscle cells (PASMCs) stimulated by TNFα 10ng/ml, pretreatment with KAG-308 significantly upregulated mRNA level of Il6 (5.9±0.1vs 1.0±0.1, p <0.05), whereas downregulated Ki67 (0.4±0.1 vs 1.0±0.2, p <0.05), suggesting anti-proliferative effect via non-inflammatory pathway. Conclusions: KAG-308 ameliorated pulmonary vascular remodeling and PH in MCT-exposed rat, whereas it didn’t show anti-inflammatory effect but anti-proliferative effect in human PASMCs. Although EP 4 agonist KAG-308 could be a potential therapeutic agent for the treatment of PAH, the mechanism of anti-proliferation remains to be elucidated.