III 型肺动脉高压患者血管平滑肌中 PGI 和 ET-1 通路的相互作用。
Interaction between PGI and ET-1 pathways in vascular smooth muscle from Group-III pulmonary hypertension patients.
机构信息
Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul 34116, Turkey.
Université de Paris, INSERM, UMR-S 1148, CHU X. Bichat, 75018 Paris, France; Paris 13 University, 93430 Villetaneuse, France.
出版信息
Prostaglandins Other Lipid Mediat. 2020 Feb;146:106388. doi: 10.1016/j.prostaglandins.2019.106388. Epub 2019 Oct 28.
Pulmonary hypertension (PH) is characterized by an elevation of mean pulmonary artery pressure and it is classified into five groups. Among these groups, PH Group-III is defined as PH due to lung disease or hypoxia. Prostacyclin (PGI) analogues (iloprost, treprostinil) and endothelin-1 (ET-1) receptor antagonists (ERA) (used alone or in combination) are therapies used for treating PH. The mechanisms underlying the positive/negative effects of combination treatment are not well documented, and in this study, we tested the hypothesis that the combination of a PGI analogue (iloprost, treprostinil) and an ERA may be more effective than either drug alone to treat vasculopathies observed in PH Group-III patients. Using Western blotting, ET and ET receptor expression were determined in human pulmonary artery (HPA) preparations derived from control and PH Group-III patients, and the physiologic impact of altered expression ratios was assessed by measuring ET-1 induced contraction of ex vivo HPA and human pulmonary veins (HPV) in an isolated organ bath system. In addition, the effects of single agent or combination treatments with a PGI analogue and an ERA on ET-1 release and HPA smooth muscle cells (hPASMCs) proliferation were determined by ELISA and MTT techniques, respectively. Our results indicate that the increased ET/ET receptor expression ratio in HPA derived from PH Group-III patients is primarily governed by a greatly depressed ET receptor expression. However, contractions induced by ET-1 are not impacted in HPA and HPV derived from PH Group-III patients as compared to controls. Also, we found that the combination of an ET receptor antagonist (BQ123) with iloprost provides greater inhibition of hPASMCs proliferation (-48±14% control; -32±06% PH) than either agent alone. Of note, while the ET receptor antagonist (BQ788) increases ET-1 production from PH Group-III patients' preparations (HPA, parenchyma), even under these more proliferative conditions, iloprost and treprostinil are still effective to inhibit hPASMCs proliferation (-22/-24%). Our findings may provide new insights for the treatment of PH Group-III by combining a PGI analogue and a selective ET receptor antagonist.
肺动脉高压（PH）的特征是平均肺动脉压升高，并分为五组。在这些组中，PH 组 III 被定义为由于肺部疾病或缺氧引起的 PH。前列环素（PGI）类似物（依前列醇、曲前列尼尔）和内皮素-1（ET-1）受体拮抗剂（ERA）（单独使用或联合使用）是用于治疗 PH 的疗法。联合治疗的积极/消极影响的机制尚未得到很好的记录，在这项研究中，我们测试了这样一个假设，即 PGI 类似物（依前列醇、曲前列尼尔）和 ERA 的联合治疗可能比单独使用任何一种药物更有效，以治疗 PH 组 III 患者中观察到的血管病变。通过 Western blot 法，测定了来自对照和 PH 组 III 患者的人肺动脉（HPA）制剂中的 ET 和 ET 受体表达，并通过在离体器官浴系统中测量 ET-1 诱导的 HPA 和人肺静脉（HPV）收缩来评估改变的表达比值的生理影响。此外，通过 ELISA 和 MTT 技术分别测定了单一药物或联合治疗 PGI 类似物和 ERA 对 ET-1 释放和 HPA 平滑肌细胞（hPASMCs）增殖的影响。我们的结果表明，来自 PH 组 III 患者的 HPA 中增加的 ET/ET 受体表达比值主要由 ET 受体表达大大降低所控制。然而，与对照组相比，来自 PH 组 III 患者的 HPA 和 HPV 诱导的收缩不受影响。此外，我们发现，ET 受体拮抗剂（BQ123）与依前列醇联合使用可更有效地抑制 hPASMCs 增殖（对照为-48±14%；PH 为-32±06%），而单独使用任何一种药物效果都不佳。值得注意的是，虽然 ET 受体拮抗剂（BQ788）增加了来自 PH 组 III 患者的制剂（HPA、实质）中的 ET-1 产生，但即使在这些更增殖的条件下，依前列醇和曲前列尼尔仍能有效抑制 hPASMCs 增殖（-22/-24%）。我们的发现可能为通过联合使用 PGI 类似物和选择性 ET 受体拮抗剂治疗 PH 组 III 提供新的见解。
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