Dannewitz Prosseda Svenja, Ali Md Khadem, Spiekerkoetter Edda
Division Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford, CA 94305, USA.
Genes (Basel). 2020 Dec 23;12(1):8. doi: 10.3390/genes12010008.
Pulmonary Arterial Hypertension (PAH) is a disease of the pulmonary arteries, that is characterized by progressive narrowing of the pulmonary arterial lumen and increased pulmonary vascular resistance, ultimately leading to right ventricular dysfunction, heart failure and premature death. Current treatments mainly target pulmonary vasodilation and leave the progressive vascular remodeling unchecked resulting in persistent high morbidity and mortality in PAH even with treatment. Therefore, novel therapeutic strategies are urgently needed. Loss of function mutations of the Bone Morphogenetic Protein Receptor 2 (BMPR2) are the most common genetic factor in hereditary forms of PAH, suggesting that the BMPR2 pathway is fundamentally important in the pathogenesis. Dysfunctional BMPR2 signaling recapitulates the cellular abnormalities in PAH as well as the pathobiology in experimental pulmonary hypertension (PH). Approaches to restore BMPR2 signaling by increasing the expression of BMPR2 or its downstream signaling targets are currently actively explored as novel ways to prevent and improve experimental PH as well as PAH in patients. Here, we summarize existing as well as novel potential treatment strategies for PAH that activate the BMPR2 receptor pharmaceutically or genetically, increase the receptor availability at the cell surface, or reconstitute downstream BMPR2 signaling.
肺动脉高压（PAH）是一种肺动脉疾病，其特征是肺动脉管腔逐渐变窄，肺血管阻力增加，最终导致右心室功能障碍、心力衰竭和过早死亡。目前的治疗主要针对肺血管舒张，而对进行性血管重塑未加控制，导致即使经过治疗，PAH的发病率和死亡率仍然居高不下。因此，迫切需要新的治疗策略。骨形态发生蛋白受体2（BMPR2）功能丧失突变是遗传性PAH最常见的遗传因素，这表明BMPR2信号通路在发病机制中至关重要。功能失调的BMPR2信号传导概括了PAH中的细胞异常以及实验性肺动脉高压（PH）中的病理生物学。目前正在积极探索通过增加BMPR2或其下游信号靶点的表达来恢复BMPR2信号传导的方法，作为预防和改善实验性PH以及患者PAH的新途径。在这里，我们总结了现有的以及新的潜在PAH治疗策略，这些策略通过药物或基因方式激活BMPR2受体，增加受体在细胞表面的可用性，或重建下游BMPR2信号传导。
