Yin Qin, Peng Wanhong, Yang Jie, Fan Cunyu, Wang Qinru, Gan Hongyu, Zhang Shiwei, Fan Xiaohang, Li Fajiu
Department of Respiratory and Critical Care Medicine, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, 430015, Hubei, China.
Department of Radiology, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, 430015, Hubei, China.
J Nat Med. 2025 Jun 29. doi: 10.1007/s11418-025-01921-7.
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.
肺动脉高压是一种诊断复杂、治疗具有挑战性且临床药物短缺的疾病。其中，由肺部疾病和/或缺氧引起的III组肺动脉高压患者数量位居第二。目前，针对III组肺动脉高压的临床指导用药极少，且疗效有限。迫切需要寻找新的有效药物。为了探究诺米林治疗缺氧诱导的肺动脉高压的潜在疗效及其潜在机制，通过连续6周缺氧复制缺氧诱导的肺动脉高压大鼠模型。每天通过灌胃给予诺米林或西地那非，持续2周。随后，测量血流动力学参数、HE染色和Masson染色、肺动脉平滑肌细胞（PASMCs）的细胞质钙水平。此外，进行细胞热位移分析、细胞迁移和增殖分析以及免疫印迹，以探究其治疗效果和潜在机制。诺米林有效减轻大鼠缺氧诱导的肺动脉高压，导致平均肺动脉压、肺血管阻力降低，血管重塑改善。此外，诺米林有效抑制缺氧诱导的细胞内钙水平升高、PASMCs的迁移和增殖。其潜在机制归因于诺米林通过抑制钙敏感受体（CaSR）二聚体的形成来降低CaSR活性。诺米林通过抑制CaSR活性有效减轻缺氧诱导的肺动脉高压。诺米林可能是治疗III组肺动脉高压的潜在候选药物。
