Department of Medicine, University of California San Diego, La Jolla, California 92093.
Institute for Pharmacology and Toxicology, University of Bonn, 53113 Bonn, Germany.
J Biol Chem. 2013 Jun 7;288(23):16557-16566. doi: 10.1074/jbc.M113.458729. Epub 2013 Apr 23.
Pulmonary arterial hypertension (PAH) is a progressive, usually fatal disease with abnormal vascular remodeling. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients are hyperproliferative and apoptosis-resistant and demonstrate decreased signaling in response to bone morphogenetic proteins (BMPs). Cyclic GMP-elevating agents are beneficial in PAH, but their mechanism(s) of action are incompletely understood. Here we show that BMP signaling via Smad1/5/8 requires cGMP-dependent protein kinase isotype I (PKGI) to maintain PASMCs in a differentiated, low proliferative state. BMP cooperation with cGMP/PKGI was crucial for transcription of contractile genes and suppression of pro-proliferative and anti-apoptotic genes. Lungs from mice with low or absent PKGI (Prkg1(+/-) and Prkg1(-/-) mice) exhibited impaired BMP signaling, decreased contractile gene expression, and abnormal vascular remodeling. Conversely, cGMP stimulation of PKGI restored defective BMP signaling in rats with hypoxia-induced PAH, consistent with cGMP-elevating agents reversing vascular remodeling in this PAH model. Our results provide a mechanism for the therapeutic effects of cGMP-elevating agents in PAH and suggest that combining them with BMP mimetics may provide a novel, disease-modifying approach to PAH therapy.
肺动脉高压（PAH）是一种进行性的、通常致命的疾病，伴有异常的血管重塑。PAH 患者的肺动脉平滑肌细胞（PASMCs）过度增殖且凋亡抵抗，并表现出对骨形态发生蛋白（BMPs）的信号反应降低。环鸟苷酸（cGMP）升高剂对 PAH 有益，但它们的作用机制尚不完全清楚。在这里，我们表明 BMP 信号通过 Smad1/5/8 需要 cGMP 依赖性蛋白激酶同工型 I（PKGI）来维持 PASMCs 的分化和低增殖状态。BMP 与 cGMP/PKGI 的合作对于收缩基因的转录和抑制促增殖和抗凋亡基因至关重要。PKGI 低表达或缺失（Prkg1(+/-)和 Prkg1(-/-)小鼠）的小鼠肺部表现出 BMP 信号受损、收缩基因表达减少和血管重塑异常。相反，cGMP 刺激 PKGI 恢复了缺氧诱导的 PAH 大鼠中缺陷的 BMP 信号，这与 cGMP 升高剂在该 PAH 模型中逆转血管重塑的作用一致。我们的研究结果为 cGMP 升高剂在 PAH 中的治疗效果提供了一种机制，并表明将它们与 BMP 模拟物联合使用可能为 PAH 治疗提供一种新的、疾病修饰的方法。
