Chronic hypoxia decreases KV channel expression and function in pulmonary artery myocytes

Abstract

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 α-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 K(V)]; caused E mdepolarization; and increased [Ca2+]cyt in PASMCs but negligibly affected KV channel expression, increased I K(V), and induced hyperpolarization in MASMCs. These results demonstrate that chronic hypoxia selectively downregulates KV channel expression, reduces I K(V), and induces E mdepolarization 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 α-subunit mRNA expression in PASMCs and MASMCs may result from different mechanisms involved in the regulation of KV channel gene expression.