Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo. Vasorelaxation by FR proved at least as potent as the currently used triple therapy. We also provide in vivo evidence that local pulmonary application of FR prevented right ventricular systolic pressure increase in healthy mice as well as in mice suffering from hypoxia (Hx)-induced pulmonary hypertension (PH). In addition, we demonstrate that chronic application of FR prevented and also reversed Sugen (Su)Hx-induced PH in mice. We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH.

中文翻译：

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药理学 Gq 抑制可诱导强烈的肺血管舒张并逆转肺动脉高压。


肺动脉高压（PAH）是一种危及生命的疾病，生存率有限。在此，我们提出 Gq 蛋白的药理学抑制作为抵消 PAH 中肺血管收缩和肺动脉平滑肌细胞 (PASMC) 增殖/迁移的新概念。我们证明，特定的泛 Gq 抑制剂 FR900359 (FR) 在离体小鼠、猪和人类受试者的大肺动脉和小肺动脉中诱导强烈的血管舒张。事实证明，FR 的血管舒张作用至少与目前使用的三联疗法一样有效。我们还提供了体内证据，表明局部肺部应用 FR 可防止健康小鼠以及缺氧 (Hx) 诱导的肺动脉高压 (PH) 小鼠的右心室收缩压升高。此外，我们证明长期应用 FR 可以预防并逆转 Sugen (Su)Hx 诱导的小鼠 PH。我们还证明 Gq 抑制可减少体外 PASMC 的增殖和迁移。因此，我们的工作说明了 Gq 蛋白在肺血管收缩和重塑中的主导作用，并提出直​​接 Gq 抑制作为 PH 的强大药理学策略。