The calcium release-activated calcium channel protein 1 (Orai1) could be a potential therapeutic target for pulmonary arterial hypertension (PAH), according to a new study published in Circulation Research.
“Pharmacological inhibition of Orai1 in vivo improves pulmonary vascular remodeling, right ventricular fibrosis, and hypertrophy and reduces the development of experimental PAH,” the study’s authors said.
Masson et al found that Orai1 was upregulated in lung tissues and pulmonary artery smooth muscle cells (PASMCs) from patients with PAH, compared to control subjects.
The expression of Orai1 was associated with enhanced proliferation and migration and resistance to apoptosis of PASMCs. Moreover, it was shown to promote pulmonary vasoconstriction. The prosurvival effect of Orai1 in PASMCs of patients with PAH is achieved, at least in part, by increasing mitochondrial Ca2+ uptake.
Orai1 downregulation, via either small interfering RNA (siRNA) or pharmacological inhibition, decreased store-operated Ca2+ entry (SOCE) and reduced proliferation and migration of PASMCs in patients with PAH. Moreover, it reduced the activity of the Ca2+-dependent serine/threonine phosphatase calcineurin by 50%. Orai1 knockdown also increased the expression of the cell cycle inhibitor protein p21 and promoted p38-mediated signaling and caspase-9 activity.
“Since we demonstrated that Orai1 contributes to PAH development, it would be interesting to test the different Orai1 inhibitors in PAH, especially since good safety in humans has been already demonstrated in several phase 1 and 2 clinical trials,” the authors said. In this study, pharmacological inhibition of Orai1 was achieved using 3 inhibitors: BTP2, JPIII, and 5J4.
Molecular studies suggested that Orai1 expression and activity in PASMCs are regulated via MEK1/2 signaling, nuclear factor of activated T cells, and nuclear factor-kappa B. In vivo studies were performed in rat models of pulmonary hypertension induced by chronic hypoxia, monocrotaline, or Sugen/hypoxia.
Masson B, Le Ribeuz H, Sabourin J, et al. Orai1 inhibitors as potential treatments for pulmonary arterial hypertension. Circ Res. Published online September 27, 2022. doi:10.1161/CIRCRESAHA.122.321041