Hypoxia inhibits gene expression of voltage-gated K+ channel alpha subunits in pulmonary artery smooth muscle cells.
Activity of voltage-gated K+ channels (KV) in pulmonary arterial smooth muscle cells (PASMC) is pivotal in controlling membrane potential, cytoplasmic free Ca2+ concentration ([Ca2+]cyt, and pulmonary vasomotor tone. Acute hypoxia selectively inhibits KV channels, depolarizes PASMC, raises [Ca2+]cyt, and causes pulmonary vasoconstriction and vascular remodeling. Prolonged hypoxia (24-60 h) decreased significantly the mRNA levels of KV channel alpha subunits, KV1.2 and KV1.5. Consistently, the protein levels of KV1.2 and KV1.5 were also decreased significantly by hypoxia (48-72 h). Nevertheless, hypoxia affected negligibly the mRNA levels of KV channel beta subunits (KVbeta1, KVbeta2, and KVbeta3). The native K+ channels are composed of pore-forming alpha and auxiliary beta subunits. Assembly of KV beta subunits with alpha subunits confers rapid inactivation on the slowly or non-inactivating delayed rectifier KV channels. KV beta subunits also function as an open-channel blocker of KV channels. Thus, the diminished transcription and expression of KV alpha subunits may reduce the number of KV channels and decrease KC currents. Unchanged transcription of KV beta subunits may increase the fraction of the KV channel alpha subunits that are associated with beta subunits and further reduce the total KV currents. These data demonstrate a novel mechanism by which chronic hypoxia may cause pulmonary vasoconstriction and hypertension.
Wang
J
J
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
Juhaszova
M
M
Rubin
L J
LJ
Yuan
X J
XJ
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D015870:Gene Expression; D000860:Hypoxia / Q000235:genetics*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D011651:Pulmonary Artery / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014158:Transcription, Genetic
D015221:Potassium Channels; D012333:RNA, Messenger