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(+) (K(V)) 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 K(V) channels (K(V)1.5, K(V)2.1 and K(V)3.4). However, no direct link among hypoxia, 15-HETE and inhibition of K(V) subtypes is established. Therefore, we investigated whether 15-LOX/15-HETE pathway contributes to the hypoxia-induced down-regulation of K(V) channels. As K(V)1.5 channel is O(2)-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 K(V)1.5 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 (I(K(V))). 15-HETE contributes to the down-regulation of K(V)1.5 channel, inhibition of I(K(V)) and increase of native pulmonary artery tension after hypoxia. Hypoxia inhibits K(V)1.5 channel through 15-LOX/15-HETE pathway.
Chu
Xiaojie
X
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Tang
Xiaobo
X
Guo
Lei
L
Bao
Hongxia
H
Zhang
Shuang
S
Zhang
Jianing
J
Zhu
Daling
D
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism; D015687:Cell Hypoxia; D015870:Gene Expression; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D051666:Kv1.5 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D011651:Pulmonary Artery / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D006893:Hydroxyeicosatetraenoic Acids; D051666:Kv1.5 Potassium Channel; D012333:RNA, Messenger; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase