Evaluating the Molecular Basis for Acute Mountain Sickness: Hypoxia Response Gene Expression Patterns in Warfighters and Murine Populations

Abstract

Acute mountain sickness (AMS) is an illness that affects many individuals at altitudes above 2,400 m (8,000 ft) resulting in decreased performance. Models that provide quantitative estimates of AMS risk are expanding, but predictive genetic models for AMS susceptibility are still under investigation. Thirty-four male U.S. Army Soldier volunteers were exposed to baseline, 3,000 m, 3,500 m, or 4,500 m altitude conditions in a hypobaric chamber and evaluated for onset of AMS symptoms. In addition, mice were evaluated at extreme hypoxia conditions equivalent to 7,600 m. Real-time polymerase chain reaction hypoxia response array was used to identify 15 genes that were activated in Soldiers and 46 genes that were activated in mice. We identified angiopoietin-like 4 (ANGPTL4) as a gene that is significantly activated in response to hypoxia (5.8-fold upregulated at 4,500 m in humans). The role of ANGPTL4 in high-altitude response has not been explored. Pretreatment of mice with fenofibrate, an ANGPTL4-activating pharmaceutical, had a considerable effect on overall hypoxia response gene expression and resulted in significantly decreased cerebral edema following exposure to hypoxia. Activation of ANGPTL4 may protect against cerebral edema by inhibiting vascular endothelial growth factor and therefore serve as a potential target for AMS prevention.