Nobiletin alleviates hypoxia-induced pulmonary hypertension by inhibiting calcium-sensing receptor

Pulmonary hypertension is a disease characterized by complex diagnosis, challenging treatment, and a shortage of clinical medications. Among them, Group III pulmonary hypertension, which is caused by lung diseases and/or hypoxia, has the second-largest number of patients. Currently, there are extremely few clinically guided medications for Group III pulmonary hypertension, and their efficacy is limited. It is urgent to find new and effective drugs. To explore the potential efficacy of nobiletin in treating hypoxia-induced pulmonary hypertension and its underlying mechanism, the hypoxia-induced pulmonary hypertension rat model was copied by 6-week consecutive hypoxia. Nobiletin or sildenafil was administered daily via gavage for 2 weeks. Subsequently, hemodynamic parameters, HE staining and Masson staining, cytoplasmic calcium level of pulmonary arterial smooth muscle cells (PASMCs) were measured. In addition, cellular thermal shift assays, cell migration and proliferation assays, and immunoblotting were performed to explore the therapeutic effects and underlying mechanisms. Nobiletin effectively attenuated hypoxia-induced pulmonary hypertension in rat, leading to a decrease in mean pulmonary artery pressure, pulmonary vascular resistance, amelioration of vascular remodeling. Furthermore, nobiletin effectively inhibited the elevation of intracellular calcium level, the migration and proliferation of PASMCs induced by hypoxia. The mechanism underlying was attributed to the fact that nobiletin reduced calcium-sensing receptor (CaSR) activity by inhibiting the formation of CaSR dimers. Nobiletin effectively alleviated hypoxia-induced pulmonary hypertension by inhibiting CaSR activity. Nobiletin may be a potential candidate for the treatment of Group III pulmonary hypertension.