Prostanoid EP4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension

Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-gamma (PPAR gamma). There is evidence of scant IP and PPAR gamma expression but stable prostanoid EP4 receptor (EP4) expression in IPAH patients. Both IP and EP4 functionally couple with stimulatory G protein (G(s)), which activates signal transduction. We investigated the effect of an EP4-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP4, and PPAR gamma expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPAR gamma but stable expression of EP4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPAR gamma in a time-and dose-dependent manner, but these effects were reversed by AH-23848 (an EP4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPAR gamma in the activity of this EP4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP4 agonist L-902,688 reverses vascular remodeling by activating PPAR gamma. This study identified a novel EP4-PKA-PPAR gamma pathway, and we propose EP4 as a potential therapeutic target for PAH.