PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation
PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation
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DOI：
10.1126/scisignal.abb3616
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发表时间：
2021-01-26
影响因子：
7.3
通讯作者：
Wada, Youichiro
中科院分区：
文献类型：
--
作者：
Shimizu, Takashi;Higashijima, Yoshiki;Wada, Youichiro
肺动脉高压（PAH）是一种以肺血管过度重构为特征的致死性疾病。然而，尽管治疗策略取得了进展，但骨形态发生蛋白受体2（BMPR 2）编码基因突变的PAH患者表现出严重的表型和结局。我们试图研究PER样激酶（PERK），参与与未折叠蛋白反应（UPR）相关的三个主要途径之一，对PAH病理生理学在BMPR 2杂合子小鼠的影响。肺动脉平滑肌细胞（PASMCs）中BMPR 2杂合性通过PERK介导的UPR臂降低抗凋亡microRNA miR 124 - 3 p的丰度。缺氧促进BMPR 2杂合PASMCs中未折叠蛋白的积累，导致PERK信号传导、细胞活力、细胞增殖和糖酵解增加。蛋白质组学分析显示，PERK消融抑制了缺氧BMPR 2杂合PASMCs中的PDGFRD-STAT 1信号传导和糖酵解。此外，PERK消融或PERK抑制改善了肺动脉高压Sugen/慢性缺氧模型中的肺血管重塑，与BMPR 2状态无关。因此，这些研究结果表明，PERK抑制是有或无BMPR 2突变的PAH患者的一种有前途的治疗策略。
Pulmonary arterial hypertension (PAH) is a fatal disease characterized by excessive pulmonary vascular remodeling. However, despite advances in therapeutic strategies, patients with PAH bearing mutations in the bone morphogenetic protein receptor type 2 (BMPR2)-encoding gene present severe phenotypes and outcomes. We sought to investigate the effect of PER-like kinase (PERK), which participates in one of three major pathways associated with the unfolded protein response (UPR), on PAH pathophysiology in BMPR2 heterozygous mice. BMPR2 heterozygosity in pulmonary artery smooth muscle cells (PASMCs) decreased the abundance of the antiapoptotic microRNA miR124-3p through the arm of the UPR mediated by PERK. Hypoxia promoted the accumulation of unfolded proteins in BMPR2 heterozygous PASMCs, resulting in increased PERK signaling, cell viability, cellular proliferation, and glycolysis. Proteomic analyses revealed that PERK ablation suppressed PDGFRD-STAT1 signaling and glycolysis in hypoxic BMPR2 heterozygous PASMCs. Furthermore, PERK ablation or PERK inhibition ameliorated pulmonary vascular remodeling in the Sugen/chronic hypoxia model of PAH, irrespective of BMPR2 status. Hence, these findings suggest that PERK inhibition is a promising therapeutic strategy for patients with PAH with or without BMPR2 mutation.