Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC, Québec, Canada.
Department of Medicine, Université Laval, QC, Québec, Canada.
J Mol Med (Berl). 2018 Feb;96(2):223-235. doi: 10.1007/s00109-017-1619-0. Epub 2017 Dec 30.
Pulmonary arterial hypertension (PAH) is a progressive vascular remodeling disease characterized by a persistent elevation of pulmonary artery pressure, leading to right heart failure and premature death. Exaggerated proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is a key component of vascular remodeling. Despite major advances in the field, current therapies for PAH remain poorly effective in reversing the disease or significantly improving long-term survival. Because the transcription factor FOXM1 is necessary for PASMC proliferation during lung morphogenesis and its overexpression stimulates proliferation and evasion of apoptosis in cancer cells, we thus hypothesized that upregulation of FOXM1 in PAH-PASMCs promotes cell expansion and vascular remodeling. Our results showed that FOXM1 was markedly increased in distal pulmonary arteries and isolated PASMCs from PAH patients compared to controls as well as in two preclinical models. In vitro, we showed that miR-204 expression regulates FOXM1 levels and that inhibition of FOXM1 reduced cell proliferation and resistance to apoptosis through diminished DNA repair mechanisms and decreased expression of the pro-remodeling factor survivin. Accordingly, inhibition of FOXM1 with thiostrepton significantly improved established PAH in two rat models. Thus, we show for the first time that FOXM1 is implicated in PAH development and represents a new promising target.
FOXM1 is overexpressed in human PAH-PASMCs and PAH animal models. FOXM1 promotes PAH-PASMC proliferation and resistance to apoptosis. Pharmacological inhibition of FOXM1 improves established PAH in the MCT and Su/Hx rat models. FOXM1 may be a novel therapeutic target in PAH.
肺动脉高压（PAH）是一种进行性血管重构疾病，其特征为肺动脉压持续升高，导致右心衰竭和过早死亡。肺动脉平滑肌细胞（PASMC）的过度增殖和抗凋亡是血管重构的关键组成部分。尽管在该领域取得了重大进展，但目前治疗 PAH 的方法仍难以有效逆转疾病或显著改善长期生存率。由于转录因子 FOXM1 是肺形态发生过程中 PASMC 增殖所必需的，并且其过表达刺激癌细胞增殖和逃避凋亡，因此我们假设 PAH-PASMC 中的 FOXM1 上调促进细胞扩张和血管重构。我们的研究结果表明，与对照组相比，PAH 患者的远端肺动脉和分离的 PASMC 以及两种临床前模型中 FOXM1 的表达明显增加。在体外，我们表明 miR-204 的表达调节 FOXM1 的水平，并且 FOXM1 的抑制通过减少 DNA 修复机制和降低促重构因子 survivin 的表达来减少细胞增殖和抗凋亡。因此，用硫代丝菌素抑制 FOXM1 可显著改善两种大鼠模型中的已建立的 PAH。因此，我们首次表明 FOXM1 参与 PAH 的发展，并代表了一个新的有希望的靶标。
FOXM1 在人 PAH-PASMCs 和 PAH 动物模型中过度表达。FOXM1 促进 PAH-PASMC 的增殖和抗凋亡。FOXM1 的药物抑制可改善 MCT 和 Su/Hx 大鼠模型中的已建立的 PAH。FOXM1 可能是 PAH 的一种新的治疗靶标。
