Role of the prostanoid EP4 receptor in iloprost-mediated vasodilatation in pulmonary hypertension
Role of the prostanoid EP4 receptor in iloprost-mediated vasodilatation in pulmonary hypertension
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DOI：
10.1164/rccm.200710-1519oc
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发表时间：
2008-07-15
影响因子：
24.7
通讯作者：
Schermuly, Ralph Theo
中科院分区：
文献类型：
--
作者：
Lai, Ying-Ju;Pullamsetti, Soni Savai;Schermuly, Ralph Theo
依据伊洛前列素可有效治疗肺动脉高压。它通过结合前列环素受体（IP受体）升高CAMP发挥作用。然而，有证据表明，严重肺动脉高压患者在重塑的肺动脉平滑肌中IP受体的表达降低。目的：我们假设除了IP受体之外，前列腺素受体也参与了伊洛前列素的信号转导。采用免疫印迹法检测特发性肺动脉高压患者肺组织IP和前列腺素EP 4受体，用免疫组织化学方法检测野百合碱（MCT 28 d）处理的大鼠肺组织中的受体。从对照组和用AH 6809（EP 2受体拮抗剂）和AH 23848（EP 4受体拮抗剂）与伊洛前列素联合治疗的MCT 28 d大鼠的肺动脉平滑肌细胞（PASMC）中分离蛋白质和mRNA。细胞内cAMP也在这些tissues.Measurements和主要结果：IP受体的表达减少特发性肺动脉高压患者肺样品和MCT 28天大鼠肺与对照组相比。逆转录-聚合酶链反应和免疫印迹显示，与对照组相比，MCT 28 d大鼠PASMC提取物的IP受体表达不足，但EP 4受体表达稳定。AH 23848可剂量依赖性地降低Iloprost诱导的PASMCs细胞内cAMP水平升高，而AH 6809则无此作用。结论：Iloprost通过EP 4受体介导肺动脉高压患者IP受体表达降低时的血管舒张功能。这是伊洛前列素以前未认识到的机制，并说明EP 4受体可能是治疗肺动脉高压的新治疗方法。
Rationale Iloprost is effective for the treatment of pulmonary hypertension. It acts through elevation of CAMP by binding to the prostacyclin receptor (IP receptor). However, there is evidence that patients with severe pulmonary hypertension have decreased expression of the IP receptor in the remodeled pulmonary arterial smooth muscle.Objectives: We hypothesized that prostanoid receptors other than the IP receptor are involved in signal transduction by iloprost.Methods: Immunoblotting was used to detect the IP and prostanoid EP4 receptor in lung tissue from patients with idiopathic pulmonary arterial hypertension, and immunohistochemistry was used to detect these receptors in lung sections from rats treated with monocrotaline (MCT28d). Protein and mRNA were isolated from pulmonary arterial smooth muscle cells (PASMCs) from control and MCT28d rats treated with AH6809 (an EP2 receptor antagonist) and AH23848 (an EP4 receptor antagonist) in combination with iloprost. Intracellular cAMP was also assessed in these tissues.Measurements and Main Results: IP receptor expression was reduced in idiopathic pulmonary arterial hypertension patient lung samples and MCT28d rat lungs compared with the controls. Reverse transcriptase-polymerase chain reaction and immunoblotting of MCT28d rat PASMC extracts revealed scant expression of the IP receptor but stable expression of EP4 receptor, compared with controls. Iloprost-induced elevation in intracellular CAMP in PASMCs was dose-dependently reduced by AH23848, but not by AH6809.Conclusions: Iloprost mediates vasodilatory functions via the EP4 receptor in the case of low IP receptor expression associated with pulmonary arterial hypertension. This is a previously unrecognized mechanism for iloprost, and illustrates that the EP4 receptor may be a novel therapeutic approach for the treatment of pulmonary arterial hypertension.