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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation. / Shimizu, Takashi; Higashijima, Yoshiki; Kanki, Yasuharu; Nakaki, Ryo; Kawamura, Takeshi; Urade, Yoshihiro; Wada, Youichiro.

In: Science Signaling, Vol. 14, No. 667, eabb3616, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Shimizu, T, Higashijima, Y, Kanki, Y, Nakaki, R, Kawamura, T, Urade, Y & Wada, Y 2021, 'PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation', Science Signaling, vol. 14, no. 667, eabb3616. https://doi.org/10.1126/scisignal.abb3616

APA

Shimizu, T., Higashijima, Y., Kanki, Y., Nakaki, R., Kawamura, T., Urade, Y., & Wada, Y. (2021). PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation. Science Signaling, 14(667), [eabb3616]. https://doi.org/10.1126/scisignal.abb3616

Vancouver

Shimizu T, Higashijima Y, Kanki Y, Nakaki R, Kawamura T, Urade Y et al. PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation. Science Signaling. 2021;14(667). eabb3616. https://doi.org/10.1126/scisignal.abb3616

Author

Shimizu, Takashi ; Higashijima, Yoshiki ; Kanki, Yasuharu ; Nakaki, Ryo ; Kawamura, Takeshi ; Urade, Yoshihiro ; Wada, Youichiro. / PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation. In: Science Signaling. 2021 ; Vol. 14, No. 667.

Bibtex

@article{f4c8e42656ee406da733417c97524385,
title = "PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation",
abstract = "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. ",
author = "Takashi Shimizu and Yoshiki Higashijima and Yasuharu Kanki and Ryo Nakaki and Takeshi Kawamura and Yoshihiro Urade and Youichiro Wada",
year = "2021",
doi = "10.1126/scisignal.abb3616",
language = "English",
volume = "14",
journal = "Science Signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "667",

}

RIS

TY - JOUR

T1 - PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation

AU - Shimizu, Takashi

AU - Higashijima, Yoshiki

AU - Kanki, Yasuharu

AU - Nakaki, Ryo

AU - Kawamura, Takeshi

AU - Urade, Yoshihiro

AU - Wada, Youichiro

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1126/scisignal.abb3616

DO - 10.1126/scisignal.abb3616

M3 - Journal article

C2 - 33500333

AN - SCOPUS:85100472854

VL - 14

JO - Science Signaling

JF - Science Signaling

SN - 1945-0877

IS - 667

M1 - eabb3616

ER -

ID: 257704113