High-Altitude Hypoxia Induces Excessive Erythrocytosis in Mice via Upregulation of the Intestinal /Iron-Metabolism Pathway.

Excessive erythrocytosis (EE) is a preclinical form of chronic mountain sickness (CMS). The dysregulation of iron metabolism in high-altitude hypoxia may induce EE. The intestinal hypoxia-inducible factor 2 alpha () regulates the genes involved in iron metabolism. Considering these findings, we aimed to investigate the function and mechanism of intestinal and the iron metabolism pathway in high-altitude EE mice. C57BL/6J mice were randomized into four groups: the low-altitude group, the high-altitude group, the high-altitude + inhibitor group, and the high-altitude + vehicle group. In-vitro experiments were performed using the human intestinal cell line HCT116 cultured under hypoxic conditions for 24 h. Results showed that high-altitude hypoxia significantly increased the expression of intestinal and iron metabolism-related genes, including , , , , and in EE mice. Genetic blockade of the intestinal -iron metabolism pathway decreased iron availability in HCT116 cells during hypoxia. The inhibitor PT2385 suppressed intestinal expression, decreased iron hypermetabolism, and reduced excessive erythrocytosis in mice. These data support the hypothesis that exposure to high-altitude hypoxia can lead to iron hypermetabolism by activating intestinal transcriptional regulation, and reduced iron availability improves EE by inhibiting intestinal signaling.