Prostanoid EP4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension
Prostanoid EP4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension
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DOI：
10.1152/ajplung.00245.2017
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发表时间：
2018-03-01
影响因子：
4.9
通讯作者：
Lai, Ying-Ju
中科院分区：
文献类型：
--
作者：
Li, Hsin-Hsien;Hsu, Hsao-Hsun;Lai, Ying-Ju
结合前列环素受体（IP）刺激cAMP合成的前列环素激动剂是治疗特发性肺动脉高压（IPAH）的有效血管扩张剂，但这种信号传导可能通过核过氧化物酶体增殖体激活受体γ (PPAR γ)发生。有证据表明IPAH患者的IP和PPAR γ表达不足，但前列腺素EP4受体（EP4）表达稳定。IP和EP4都与刺激G蛋白（G(s)）偶联，激活信号转导。我们研究了ep4特异性激动剂对肺动脉重塑的影响及其在肺动脉平滑肌细胞（PASMCs）中的调节机制。免疫印迹法显示，IP、EP4和PPAR γ在人肺动脉高压（PAH）和单罗塔林（MCT）诱导的PAH大鼠肺组织中表达。采用选择性EP4激动剂L-902,688处理mct诱导的PAH大鼠（MCT-PASMCs）分离的PASMCs，研究其抗血管重构作用。IPAH患者肺组织和mct - pasmc中，IPAH和PPAR γ表达不足，而EP4表达稳定。L-902,688通过激活PPAR γ以时间和剂量依赖的方式抑制ip不足的MCT-PASMC的增殖和迁移，但这些作用被AH-23848（一种EP4拮抗剂）和H-89（一种蛋白激酶a （PKA）抑制剂）逆转，突出了PPAR γ在这种EP4激动剂活性中的关键作用。L-902,688对低氧PAH小鼠和mct诱导的PAH大鼠肺动脉重构的影响因此，我们得出结论，选择性EP4激动剂L-902,688通过激活PPAR γ逆转血管重构。本研究发现了一个新的EP4- pka - ppar γ通路，我们认为EP4可能是PAH的潜在治疗靶点。
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.