PERK inhibition attenuates vascular remodeling in pulmonary arterial hypertension caused by BMPR2 mutation.
Takashi ShimizuYoshiki HigashijimaYasuharu KankiRyo NakakiTakeshi KawamuraYoshihiro UradeYouichiro WadaPublished in: Science signaling (2021)
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.
Keyphrases
- pulmonary arterial hypertension
- endoplasmic reticulum stress
- pulmonary artery
- pulmonary hypertension
- endoplasmic reticulum
- early onset
- polycyclic aromatic hydrocarbons
- signaling pathway
- cell proliferation
- small molecule
- type diabetes
- coronary artery
- physical activity
- weight gain
- adipose tissue
- gene expression
- binding protein
- copy number
- protein kinase
- dna methylation
- amino acid
- atrial fibrillation
- high fat diet induced