肺动脉高压
蛋白质亚单位
生物
疾病
信号转导
细胞生物学
肺病
医学
化学
内科学
生物化学
基因
作者
Eva Berghausen,Wiebke Janssen,Marius Vantler,Leoni Gnatzy-Feik,M Krause,Arnica Behringer,Christine G. Joseph,Mario Zierden,Henrik ten Freyhaus,Anna Klinke,Stephan Baldus,Miguel A. Alejandre Alcázar,Rajkumar Savai,Dickson W.L. Wong,Peter Boor,Jean J. Zhao,Ralph T. Schermuly,Stephan Rosenkranz
摘要
Enhanced signaling via RTKs in pulmonary hypertension (PH) impedes current treatment options because it perpetuates proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Here, we demonstrated hyperphosphorylation of multiple RTKs in diseased human vessels and increased activation of their common downstream effector phosphatidylinositol 3'-kinase (PI3K), which thus emerged as an attractive therapeutic target. Systematic characterization of class IA catalytic PI3K isoforms identified p110α as the key regulator of pathogenic signaling pathways and PASMC responses (proliferation, migration, survival) downstream of multiple RTKs. Smooth muscle cell-specific genetic ablation or pharmacological inhibition of p110α prevented onset and progression of pulmonary hypertension (PH) as well as right heart hypertrophy in vivo and even reversed established vascular remodeling and PH in various animal models. These effects were attributable to both inhibition of vascular proliferation and induction of apoptosis. Since this pathway is abundantly activated in human disease, p110α represents a central target in PH.
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