The first selective inhibitor of protein kinase R- (PKR)-like endoplasmic reticulum kinase (PERK), GSK-2606414, has been shown to attenuate vascular remodeling in pulmonary arterial hypertension (PAH) in mice, according to a study reported in the January 26, 2021, edition of Science Signaling.
The study's findings suggest that PERK inhibition may be a promising therapeutic strategy for PAH patients with the bone morphogenetic protein receptor type 2 (BMPR2) mutation who, despite advances in therapeutic strategies, have more severe phenotypes and poorer outcomes.
"This the first study to show that PERK inhibition attenuates vascular remodeling in PAH and that mice with the BMPR2 mutation develop more a more severe phenotype than wild-type (WT) mice," said study leader Takashi Shimizu.
"Current PAH treatments include vasodilators, such as prostaglandin I2 and endothelin receptor antagonists, but these are ineffective for PAH with the BMPR2 mutation, hence the need for new treatments for mutation carriers," said the postdoctoral fellow in the Isotope Science Center at The University of Tokyo (UT) and the Department of Cardiovascular Medicine at UT Graduate School of Medicine.
PAH is a fatal disease causing pulmonary vascular destruction due to endothelial dysfunction and progressive proliferative media thickness, which eventually leads to hypoxemia and systematic metabolic abnormalities, including aerobic glycolysis and multiple organ dysfunction.
Germline BMPR2 mutations occur in about 80% of patients with heritable PAH and 20% of those with idiopathic disease, with BMP signaling playing a key role in vascular homeostasis by inhibiting abnormal pulmonary vascular remodeling (PVR).
These mutations alter responses to BMPs, resulting in PVR via increased apoptosis of pulmonary vascular endothelial cells and uncontrolled proliferation of pulmonary artery (PA) smooth muscle cells (PASMCs).
In PAH patients, PASMCs show a shift in glucose metabolism from oxidative phosphorylation to glycolysis, which is predominately regulated by signal transducer and activator of transcription 1 (STAT1), phosphorylation of which induces a signaling cascade leading to cell growth and glycolysis.
This suggests that in PASMCs, hypoxia-induced PERK activation combined with BMPR2 mutations might drive PAH pathogenesis and that PERK inhibition in PASMCs caused by BMPR2 mutation may ameliorate PVR, suppressing glycolysis.
In their new Science Signaling study, Shimizu and colleagues performed a series of in vivo and in vitro experiments to evaluate the importance of this pathway and the efficiency of PERK inhibitors, such as GSK-2606414.
Specifically, the researchers investigated the effect of PERK, which participates in one of three major pathways associated with the unfolded protein response (UPR), on PAH pathophysiology in BMPR2 heterozygous mice.
"The UPR is a cellular stress response related to endoplasmic reticulum (ER) stress, with the UPR already having been shown to plays a role in PAH pathophysiology in mice without mutations," Shimizu told BioWorld.
"It has also reported that EIF2 signaling downstream of PERK is the most advanced in human pulmonary artery smooth muscle cells containing a BMPR2 mutation, but our study is the first to show that PERK controls cell proliferation in PASMCs with BMPR2 mutations under hypoxia."
BMPR2 heterozygosity in PASMCs was also shown to decrease the abundance of the anti-apoptotic microRNA, miR124-3p by approximately 70%, through the UPR arm mediated by PERK.
"MiR124-3p is the most inhibited miRNA in pulmonary endothelial cells with the BMPR2 mutation and is the strongest suppressor of ER stress-induced apoptosis," noted Shimizu.
Hypoxia promoted the accumulation of unfolded proteins in BMPR2 heterozygous PASMCs, resulting in increased PERK signaling, cell viability, cellular proliferation, and glycolysis.
Proteomic analyses then revealed that tamoxifen-induced PERK ablation suppressed STAT1 phosphorylation, signaling and glycolysis in hypoxic BMPR2 heterozygous PASMCs.
Furthermore, PERK ablation or PERK inhibition with GSK-2606414 was shown to ameliorate PVR in a chronic hypoxia mouse model of PAH, irrespective of the BMPR2 status, suggesting that PERK inhibition is a promising therapeutic strategy for PAH patients with or without the BMPR2 mutation.
Regarding the PERK inhibitor's further development, "GSK-2606414 was originally developed by GlaxoSmithKline as a new compound for treating neurodegenerative disorders such as Alzheimer's disease and has been used in healthy volunteers in the UK in phase I trials," noted Shimizu. "However, clinical trials were halted due to side effects, including weight loss and elevated blood glucose levels at high doses, causing GSK to surrender the drug's patent."
"However, we used low doses of GSK-2606414 in our experiments and no such side effects were observed. Nevertheless, stringent safety assessment of low-dose GSK-2606414 will be necessary, before it can be considered for clinical trials for PAH in humans."