Zinc Homeostasis Plays Important Roles in Hypoxia Tolerance: A Study Conducted Clinically and In Vitro.

Guo, Yan, Chao Yu, Zhongsheng Lu, Menglan Zhang, Qiang Zhang, and Xiao Liu. Zinc homeostasis plays important roles in hypoxia tolerance: A study conducted clinically and in vitro. High Alt Med Biol. 00:00-00, 2024. Objective: High-altitude environments pose significant challenges to human physiology due to reduced oxygen availability, often resulting in altitude-related illnesses such as high-altitude cerebral edema (HACE). This study focuses on understanding the role of zinc homeostasis in enhancing hypoxia tolerance, which may be pivotal in mitigating the adverse effects of such illnesses. Methods: The study involved healthy individuals from high-altitude (4,500-5,000 m) and low-altitude areas (0-200 m), as well as patients with HACE. Blood samples were collected and analyzed. Additionally, a hypoxic model was developed using human brain microvascular endothelial cells (HBMECs), and zinc intervention was implemented. Results: In the blood samples of patients with HACE and those of healthy individuals, there were over 4,000 differentially expressed genes (DEGs), with more than 300 of them linked to zinc. Among these zinc-associated genes, only carbonic anhydrase I (CA1) exhibited a substantial upregulation in expression, while the expression of others was notably downregulated. Compared with the high-altitude group, hemoglobin (Hb) (14.7 vs. 19.5 g/dl) and plasma zinc (37.0 vs. 94.0 mmol/dl) were lower in HACE, while CA1 (55.4 vs. 8.6 g/l) was elevated (p < 0.01). In vitro studies confirmed that exposure to hypoxia (O₂ 8%-8.5%, 24 hours) inhibited HBMECs proliferation and migration, increased apoptosis and necrosis, and led to abnormal expression of CA1 and various zinc transport proteins. However, zinc intervention (6 μM, 24 hours) significantly mitigated these adverse effects and improved the cell's ability to tolerate hypoxia. Conclusion: Zinc homeostasis was crucial for hypoxia tolerance. Proper zinc supplementation could potentially alleviate symptoms associated with hypoxia intolerance, such as altitude sickness, but further confirmation was needed.