Chronic thromboembolic
pulmonary hypertension (CTEPH) is a group 4
pulmonary hypertension (PH) characterized by nonresolving
thromboembolism in the central pulmonary artery and vascular occlusion in the proximal and distal pulmonary artery. Medical
therapy is chosen for patients who are ineligible for pulmonary
endarterectomy or balloon pulmonary angioplasty or who have symptomatic residual PH after surgery or intervention.
Selexipag, an oral
prostacyclin receptor agonist and potent
vasodilator, was approved for CTEPH in Japan in 2021. To evaluate the pharmacological effect of
selexipag on vascular occlusion in CTEPH, we examined how its active metabolite
MRE-269 affects
platelet-derived growth factor-stimulated pulmonary arterial smooth muscle cells (PASMCs) from CTEPH patients.
MRE-269 showed a more potent antiproliferative effect on PASMCs from CTEPH patients than on those from normal subjects.
DNA-binding protein inhibitor (ID) genes ID1 and ID3 were found by
RNA sequencing and real-time quantitative polymerase chain reaction to be expressed at lower levels in PASMCs from CTEPH patients than in those from normal subjects and were upregulated by
MRE-269 treatment. ID1 and ID3 upregulation by
MRE-269 was blocked by co-incubation with a
prostacyclin receptor antagonist, and ID1 knockdown by
small interfering RNA transfection attenuated the antiproliferative effect of
MRE-269. ID signaling may be involved in the antiproliferative effect of
MRE-269 on PASMCs. This is the first study to demonstrate the pharmacological effects on PASMCs from CTEPH patients of a
drug approved for the treatment of CTEPH. Both the vasodilatory and the antiproliferative effect of
MRE-269 may contribute to the efficacy of
selexipag in CTEPH.