Chronic hypoxia decreases K(V) channel expression and function in pulmonary artery myocytes.
Activity of voltage-gated K+ (KV) channels regulates membrane potential (E(m)) and cytosolic free Ca2+ concentration ([Ca2+](cyt)). A rise in ([Ca2+](cyt))in pulmonary artery (PA) smooth muscle cells (SMCs) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. Chronic hypoxia (PO(2) 30-35 mmHg for 60-72 h) decreased mRNA expression of KV channel alpha-subunits (Kv1.1, Kv1.5, Kv2.1, Kv4.3, and Kv9.3) in PASMCs but not in mesenteric artery (MA) SMCs. Consistently, chronic hypoxia attenuated protein expression of Kv1.1, Kv1.5, and Kv2.1; reduced KV current [I(KV)]; caused E(m) depolarization; and increased ([Ca2+](cyt)) in PASMCs but negligibly affected KV channel expression, increased I(KV), and induced hyperpolarization in MASMCs. These results demonstrate that chronic hypoxia selectively downregulates KV channel expression, reduces I(KV), and induces E(m) depolarization in PASMCs. The subsequent rise in ([Ca2+](cyt)) plays a critical role in the development of pulmonary vasoconstriction and medial hypertrophy. The divergent effects of hypoxia on KV channel alpha-subunit mRNA expression in PASMCs and MASMCs may result from different mechanisms involved in the regulation of KV channel gene expression.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCSD Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-8382, USA.
O
O
Platoshyn
Y
Y
Yu
V A
VA
Golovina
S S
SS
McDaniel
S
S
Krick
L
L
Li
J Y
JY
Wang
L J
LJ
Rubin
J X
JX
Yuan
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D003600:Cytosol / Q000378:metabolism; D004594:Electrophysiology; D000860:Hypoxia / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D009994:Osmolar Concentration; D016133:Polymerase Chain Reaction; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D015221:Potassium Channels; D020033:Protein Isoforms; D012333:RNA, Messenger; D002118:Calcium