Hypoxia suppresses KV1.5 channel expression through endogenous 15-HETE in rat pulmonary artery

Hypoxia initiated pulmonary vasoconstriction is due to the inhibition of voltage-gated K+ (KV) channels. But the mechanism is unclear. We have evidence that hypoxia activates 15-lipoxygenase (15-LOX) in distal pulmonary arteries and increases the formation of 15-hydroxyeicosatetraenoate (15-HETE). 15-HETE-induced pulmonary artery constriction to be through the inhibition of KV channels (KV1.5, KV2.1 and KV3.4). However, no direct link among hypoxia, 15-HETE and inhibition of KV subtypes is established. Therefore, we investigated whether 15-LOX/15-HETE pathway contributes to the hypoxia-induced down-regulation of KV channels. As KV1.5 channel is O2-sensitive, it was chosen in the initial study. We found that inhibition of 15-LOX suppressed the response of hypoxic pulmonary artery rings to phenylephrine. The expressions of KV1.5 channel mRNA and protein was robustly up-regulated in cultured PASMC and pulmonary artery after blocking of 15-LOX by lipoxygenase inhibitors in hypoxia. The 15-LOX blockade also partly rescued the voltage-gated K+ current (IKVIKV). 15-HETE contributes to the down-regulation of KV1.5 channel, inhibition of IKVIKV and increase of native pulmonary artery tension after hypoxia. Hypoxia inhibits KV1.5 channel through 15-LOX/15-HETE pathway.