1 Division of Pulmonary and Critical Care, Department of Medicine.
2 Wall Center for Pulmonary Vascular Disease.
Am J Respir Crit Care Med. 2019 Jan 1;199(1):83-98. doi: 10.1164/rccm.201712-2553OC.
Pulmonary arterial hypertension (PAH) is characterized by progressive narrowing of pulmonary arteries, resulting in right heart failure and death. BMPR2 (bone morphogenetic protein receptor type 2) mutations account for most familial PAH forms whereas reduced BMPR2 is present in many idiopathic PAH forms, suggesting dysfunctional BMPR2 signaling to be a key feature of PAH. Modulating BMPR2 signaling is therapeutically promising, yet how BMPR2 is downregulated in PAH is unclear.
We intended to identify and pharmaceutically target BMPR2 modifier genes to improve PAH.
We combined siRNA high-throughput screening of >20,000 genes with a multicohort analysis of publicly available PAH RNA expression data to identify clinically relevant BMPR2 modifiers. After confirming gene dysregulation in tissue from patients with PAH, we determined the functional roles of BMPR2 modifiers in vitro and tested the repurposed drug enzastaurin for its propensity to improve experimental pulmonary hypertension (PH).
We discovered FHIT (fragile histidine triad) as a novel BMPR2 modifier. BMPR2 and FHIT expression were reduced in patients with PAH. FHIT reductions were associated with endothelial and smooth muscle cell dysfunction, rescued by enzastaurin through a dual mechanism: upregulation of FHIT as well as miR17-5 repression. Fhit mice had exaggerated hypoxic PH and failed to recover in normoxia. Enzastaurin reversed PH in the Sugen5416/hypoxia/normoxia rat model, by improving right ventricular systolic pressure, right ventricular hypertrophy, cardiac fibrosis, and vascular remodeling.
This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug enzastaurin as a potential novel therapeutic strategy to improve PAH.
肺动脉高压（PAH）的特征是肺血管进行性变窄，导致右心衰竭和死亡。BMPR2（骨形态发生蛋白受体 2）突变占大多数家族性 PAH 形式，而许多特发性 PAH 形式存在 BMPR2 减少，表明 BMPR2 信号功能障碍是 PAH 的一个关键特征。调节 BMPR2 信号具有治疗潜力，但 PAH 中 BMPR2 如何下调尚不清楚。
我们旨在鉴定和靶向 BMPR2 修饰基因，以改善 PAH。
我们将 >20,000 个基因的 siRNA 高通量筛选与公开可用的 PAH RNA 表达数据的多队列分析相结合，以鉴定临床相关的 BMPR2 修饰基因。在确认 PAH 患者组织中的基因失调后，我们确定了 BMPR2 修饰基因在体外的功能作用，并测试了重新利用的药物恩杂鲁胺改善实验性肺动脉高压（PH）的倾向。
我们发现 FHIT（脆性组氨酸三联体）是一种新的 BMPR2 修饰基因。BMPR2 和 FHIT 在 PAH 患者中的表达降低。FHIT 减少与内皮和平滑肌细胞功能障碍有关，恩杂鲁胺通过双重机制恢复：FHIT 上调以及 miR17-5 抑制。Fhit 小鼠表现出更严重的缺氧性 PH，并且在常氧下无法恢复。恩杂鲁胺通过改善右心室收缩压、右心室肥厚、心脏纤维化和血管重塑，逆转 Sugen5416/缺氧/常氧大鼠模型中的 PH。
这项研究强调了新型 BMPR2 修饰基因 FHIT 在 PH 中的重要性，以及重新利用药物恩杂鲁胺作为改善 PAH 的潜在新型治疗策略的临床价值。
