RhoA and Rho Kinase Activation in Human Pulmonary Hypertension Role of 5-HT Signaling
RhoA and Rho Kinase Activation in Human Pulmonary Hypertension Role of 5-HT Signaling
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DOI：
10.1164/rccm.200805-691oc
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发表时间：
2009-06-15
影响因子：
24.7
通讯作者：
Pacaud, Pierre
中科院分区：
文献类型：
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作者：
Guilluy, Christophe;Eddahibi, Saadia;Pacaud, Pierre
基本原理：肺动脉高压 (PH) 的发病机制复杂且多因素，涉及肺血管的收缩、重塑和原位血栓形成。 5-羟色胺 (5-HT) 和 Rho 激酶信号传导均可能促成这些改变。目的：研究 5-HT 转运蛋白 (5-HTT) 和 RhoA/Rho 激酶通路之间可能存在的联系，以及它们在人类和实验性 PH 进展中的作用。方法：对特发性 PH (iPH) 和 5-HTT 患者的肺、血小板和肺动脉平滑肌细胞 (PA-SMC) 进行生化和功能分析测量和主要结果：iPH 患者的肺、血小板和 PA-SMC 的特征是 RhoA 和 Rho 激酶活性显着升高，以及 5-HT 与 RhoA 结合的强烈增加，表明 RhoA 血清素化。 5-HTT 抑制剂氟西汀和 2 型转谷氨酰胺酶抑制剂单丹酰尸胺可防止 5-HT 诱导的 RhoA 血清素化和 RhoA/Rho 激酶激活，以及 5-HT 诱导的 iPH 患者 PA-SMC 增殖，这种增殖也受到 Rho 激酶抑制剂法舒地尔的抑制。在 SM22-5-HTT+ 小鼠的肺中也观察到 Rho 激酶活性、RhoA 激活和 RhoA 血清素化增加，这些小鼠在平滑肌中过度表达 5-HTT，并自发产生 PH。用法舒地尔或氟西汀治疗 SM22-5-HTT+ 小鼠可限制 PH 进展和 RhoA/Rho 激酶激活。结论：iPH 中 RhoA 和 Rho 激酶活性增加，与 RhoA 血清素化增强相关。 PH 进展过程中 5-HTT/RhoA/Rho 激酶信号传导通路直接参与 5-HT 介导的 PA-SMC 增殖和血小板激活，这表明 RhoA/Rho 激酶信号传导通路是针对 PH 的新疗法的有希望的靶点。
Rationale: The complex and multifactorial pathogenesis of pulmonary hypertension (PH) involves constriction, remodeling, and in situ thrombosis of pulmonary vessels. Both serotonin (5-HT) and Rho kinase signaling may contribute to these alterations.Objectives: To investigate possible links between the 5-HT transporter (5-HTT) and RhoA/Rho kinase pathways, as well as their involvement in the progression of human and experimental PH.Methods: Biochemical and functional analyses of lungs, platelets, and pulmonary artery smooth muscle cells (PA-SMCs) from patients with idiopathic PH (iPH) and 5-HTT overexpressing mice.Measurements and Main Results: Lungs, platelets, and PA-SMCs from patients with iPH were characterized by marked elevation in RhoA and Rho kinase activities and a strong increase in 5-HT binding to RhoA indicating RhoA serotonylation. The 5-HTT inhibitor fluoxetine and the type 2 transglutaminase inhibitor monodansylcadaverin prevented 5-HT-induced RhoA serotonylation and RhoA/Rho kinase activation, as well as 5-HT-induced proliferation of PA-SMCs from iPH patients that was also inhibited by the Rho kinase inhibitor fasudil. Increased Rho kinase activity, RhoA activation, and RhoA serotonylation were also observed in lungs from SM22-5-HTT+ mice, which overexpress 5-HTT in smooth muscle and spontaneously develop PH. Treatment of SM22-5-HTT+ mice with either fasudil or fluoxetine limited PH progression and RhoA/Rho kinase activation.Conclusions: RhoA and Rho kinase activities are increased in iPH, in association with enhanced RhoA serotonylation. Direct involvement of the 5-HTT/RhoA/Rho kinase signaling pathway in 5-HT-mediated PA-SMC proliferation and platelet activation during PH progression identify RhoA/Rho kinase signaling as a promising target for new treatments against PH.