Zinc homeostasis plays important roles in hypoxia tolerance, a study conducted clinically and in vitro

Abstract

Abstract Objective: To investigate the relationship between zinc homeostasis and hypoxia tolerance. Methods: Healthy individuals from highland (4500-5000 m, the QH group) and plain (0-200 m, the HH group), as well as high-altitude cerebral edema (HACE) patients. Blood samples were analyzed and transcriptome sequenced. Develop hypoxic model in human brain microvascular endothelial cells (HBMECs), intervene with zinc. Results: The HACE group demonstrated significant changes in blood transcriptome. Out of over 4000 differentially expressed genes (DEGs) (|log2FC|>2, padj<0.05), more than 300 DEGs were zinc-related, with only the CA1 mRNA being upregulated (log2FC=5.84). Other zinc-related genes showed a more than fourfold reduction in transcription levels, including various zinc-containing enzymes and zinc transport proteins (ZTPs). Compared to QH, the RBC of HACE showed no change (5.6 vs 5.7, P>0.05). However, Hb (147 vs 195) and plasma zinc (37.0 vs 94.0) were reduced, while CA1 (55.4 vs 8.6) and HIF-1α (260 vs 48) were elevated (P<0.01). In vitro studies confirmed that hypoxic exposure (O2 8-8.5%, 24 h) hindered HBMECs proliferation and migration, increased apoptosis and necrosis, and resulted in abnormal expression of CA1 and various ZTPs. Zinc intervention (6 μM, 24 h) significantly reduced these adverse effects, enhancing the cell's tolerance to hypoxia. Conclusion: During low oxygen periods, the increase in RBC and Hb needs ample zinc and balanced homeostasis. Lack of zinc can disrupt this balance, alter transport proteins and enzyme expression, and possibly lead to severe conditions like HACE. Therefore, maintaining zinc balance is crucial for tolerance to low oxygen.