Hypoxia inhibits gene expression of voltage-gated K+ channel alpha subunits in pulmonary artery smooth muscle cells

Activity of voltage-gated K+ channels (K-v) 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 K-v channels, depolarizes PASMC, raises [Ca2+](cyt), and causes pulnonary vasoconstriction and vascular remodeling. Prolonged hypoxia (24-60 h) decreased significantly the mRNA levels of K-v channel alpha subunits, K(v)1.2 and K(v)1.5. Consistently, the protein levels of K(v)1.2 and K(v)1.5 were also decreased significantly by hypoxia (48-72 h). Nevertheless, hypoxia affected negligibly the mRNA levels of K-v channel beta subunits (K-v beta 1, K-v beta 2, and K-v beta 3). The native K+ channels are composed of pore-forming alpha and auxiliary beta subunits. Assembly of K-v beta subunits with alpha subunits confers rapid inactivation on the slowly or non-inactivating delayed rectifier K-v channels. K-v beta subunits also function as an open-channel blocker of K-v channels. Thus, the diminished transcription and expression of K-v alpha submits may reduce the number of K-v channels and decrease K-v currents. Unchanged transcription of K-v beta subunits may increase the fraction of the K-v channel alpha subunits that are associated with beta subunits and further reduce the total K-v currents. These data demonstrate a novel mechanism by which chronic hypoxia may cause pulmonary vasoconstriction and hypertension.