Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China.
Department of Geriatrics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Fujian Hypertension Research Institute, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Clinical Research Center for Geriatric Hypertension Disease of Fujian province, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Branch of National Clinical Research Center for Aging and Medicine, The First Affiliated Hospital of Fujian Medical University, Fujian Province, Fuzhou, People's Republic of China; Department of Geriatrics, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, People's Republic of China.
J Mol Cell Cardiol. 2024 Oct;195:24-35. doi: 10.1016/j.yjmcc.2024.07.003. Epub 2024 Jul 14.
Pulmonary hypertension (PH) is characterized by excessive proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), in which inflammatory signaling caused by activation of the NF-κB pathway plays an important role. A20 is an important negative regulator of the NF-κB pathway, and zinc promotes the expression of A20 and exerts a protective effect against various diseases (e.g. COVID19) by inhibiting the inflammatory signaling. The role of A20 and intracellular zinc signaling in PH has been explored, but the extracellular zinc signaling is not well understood, and whether zinc has protective effects on PH is still elusive. Using inductively coupled plasma mass spectrometry (ICP-MS), we studied the alteration of trace elements during the progression of monocrotaline (MCT)-induced PH and found that serum zinc concentration was decreased with the onset of PH accompanied by abnormalities of other three elements, including copper, chromium, and magnesium. Zinc chloride injection with the dosage of 5 mg/kg intraperitoneally partially corrected this abnormality and inhibited the progression of PH. Zinc supplementation induced the expression of A20 in lung tissue and reduce the inflammatory responses. In vitro, zinc supplementation time-dependently upregulated the expression of A20 in PASMCs, therefore correcting the excessive proliferation and migration of cells caused by hypoxia. Using genetically encoded-FRET based zinc probe, we found that these effects of zinc ions are not achieved by entering cells, but most likely by activating cell surface zinc receptor (ZnR/GPR39). These results provide the first evidence of the effectiveness of zinc supplementation in the treatment of PH.
肺动脉高压（PH）的特征是肺动脉平滑肌细胞（PASMCs）的过度增殖和迁移，其中 NF-κB 通路激活引起的炎症信号发挥着重要作用。A20 是 NF-κB 通路的重要负调控因子，锌通过抑制炎症信号促进 A20 的表达，并对各种疾病（如 COVID19）发挥保护作用。已经探索了 A20 和细胞内锌信号在 PH 中的作用，但细胞外锌信号尚不清楚，锌对 PH 是否具有保护作用仍不清楚。我们使用电感耦合等离子体质谱法（ICP-MS）研究了 MCT 诱导的 PH 进展过程中微量元素的变化，发现血清锌浓度随着 PH 的发生而降低，同时伴有其他三种元素（包括铜、铬和镁）的异常。5mg/kg 剂量的氯化锌腹腔注射部分纠正了这种异常，并抑制了 PH 的进展。锌补充诱导肺组织中 A20 的表达，并减少炎症反应。在体外，锌补充时间依赖性地上调 PASMCs 中 A20 的表达，从而纠正缺氧引起的细胞过度增殖和迁移。使用基于基因编码的 FRET 的锌探针，我们发现锌离子的这些作用不是通过进入细胞来实现的，而是很可能通过激活细胞表面锌受体（ZnR/GPR39）来实现。这些结果为锌补充治疗 PH 的有效性提供了第一个证据。
