Hypoxia Inducible Factor is partially involved in mitochondrial and metabolic responses to hypoxia in rats DEMAREST Maud ¹ , MARCOUILLER François ¹ , SOLIZ Jorge ¹ , JOSEPH Vincent ¹ ¹ Institut universitaire de cardiologie et de pneumologie, Université Laval, Québec

High altitude environments present many constraints for mammals, the most well‐known being the lack of oxygen or hypoxia. Nevertheless, several ecological reports show that mice ( Mus musculus ) unlike rats ( Rattus norvegicus ) are present above 4000m 1 although they are not native to this environment. The associated general hypothesis is that mice are pre‐adapted to high altitude environments. There are also differences in mitochondrial 2 , ventilatory and metabolic 3 responses to hypoxia between these two species. One of the mechanisms involved in many of these responses is the hypoxia‐inducible factor HIF, which helps maintain the cell's oxygen homeostasis. What precisely are the different roles of HIF in mitochondrial, ventilatory, and metabolic responses to hypoxia in rats and mice, two species more or less adapted to high‐altitude environments? Does the pharmacological stabilization of HIF in normoxia mimic the responses observed in hypoxia? Conversely, does blocking HIF in hypoxia suppress these same responses? We measured the ventilatory and metabolic responses (whole body plethysmography) of rats (SD) and mice (FVB) under the following conditions: (i) 6h normoxia (21% O2); (ii) 6h hypoxia (10% O2); (iii) 6h normoxia with injection of deferoxamine, a HIF stabilizer (200mg/kg) and (iv) 6h hypoxia with injection of 2‐methoxyestradiol, a HIF blocker (5mg/kg). In addition, we evaluated mitochondrial respiration in homogenates of liver and cerebral cortex, two organs sensitive to hypoxia. Our preliminary results show that hypoxia increases ventilation and reduces metabolism and complex I efficiency in the cerebral cortex. Furthermore, pharmacological stabilization of HIF has no effect on the ventilatory response, but seems to mimic some mitochondrial and metabolic responses to hypoxia, whereas blocking HIF has no effect on these same responses. If in mice blocking HIF in hypoxia reduces the amplitude of the observed responses, our data will demonstrate fundamental differences in the mechanisms of responses to hypoxia between these two species that would strongly support our general hypothesis.

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