Upregulation of cardioprotective SUR2A by sub-hypoxic drop in oxygen

The effects of hypoxia on gene expression have been vigorously studied, but possible effects of small changes in oxygen tension have never been addressed. SUR2A is an atypical ABC protein serving as a regulatory subunit of sarcolemmal ATP-sensitive K⁺ (K_ATP) channels. Up-regulation of SUR2A is associated with cardioprotection and improved physical endurance. Here, we have found that a 24h-long exposure to slightly decreased ambient fractional concentration of oxygen (20% oxygen), which is an equivalent to oxygen tension at 350m above sea level, significantly increased levels of SUR2A in the heart despite that this drop of oxygen did not affect levels of O₂, CO₂ and hematocrit in the blood or myocardial levels of ATP, lactate and NAD/NADH/NAD⁺. Hearts from mice exposed to 20% oxygen were significantly more resistant to ischaemia-reperfusion when compared to control ones. Decrease in fractional oxygen concentration of just 0.9% was associated with phosphorylation of ERK1/2, but not Akt, which was essential for up-regulation of SUR2A. These findings indicate that a small drop in oxygen tension up-regulates SUR2A in the heart by activating ERK signaling pathway. This is the first report to suggest that a minimal change in oxygen tension could have a profound signaling effect.