Research ArticlePhysiology

PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation

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Science Signaling  26 Jan 2021:
Vol. 14, Issue 667, eabb3616
DOI: 10.1126/scisignal.abb3616

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Not a PERK for pulmonary arterial hypertension

The vascular remodeling that occurs in pulmonary arterial hypertension (PAH) is eventually fatal because it leads to right ventricular heart failure. PAH induces the unfolded protein response (UPR), and Shimizu et al. focused on the role of the UPR kinase PERK in PAH pathology. Genetic ablation or pharmacological inhibition of PERK limited vascular remodeling in two different mouse models of PAH and prevented mice from developing right ventricular heart failure. These effects involved suppressing the activation of PDGFRβ-STAT1 signaling and glycolysis in pulmonary artery smooth muscle cells. Thus, targeting PERK may help limit the mortality associated with PAH.


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 PDGFRβ-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.

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