PDF(Pubmed)
Abstract：
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.
摘要：
肺动脉高压（PAH）是一种生存有限的危及生命的疾病。在这里，我们提出了Gq蛋白的药理学抑制作为一个新的概念，以抵消PAH中的肺血管收缩和肺动脉平滑肌细胞（PASMC）的增殖/迁移。我们证明了特异性pan-Gq抑制剂FR900359（FR）在小鼠的大肺动脉和小肺动脉中诱导了强烈的血管舒张，猪,和离体人类受试者。FR的血管舒张被证明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，表明在健康小鼠以及患有缺氧（Hx）诱导的肺动脉高压（PH）的小鼠中，局部肺部应用FR可防止右心室收缩压升高。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。我们还证明了Gq抑制在体外降低了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，并提出了直接Gq抑制作为PH的强大药理学策略。
