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The Role of K + Channels in Determining Pulmonary Vascular Tone, Oxygen Sensing, Cell Proliferation, and Apoptosis: Implications in Hypoxic Pulmonary Vasoconstriction and Pulmonary Arterial Hypertension
Author(s) -
MOUDGIL ROHIT,
MICHELAKIS EVANGELOS D.,
ARCHER STEPHEN L.
Publication year - 2006
Publication title -
microcirculation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.793
H-Index - 83
eISSN - 1549-8719
pISSN - 1073-9688
DOI - 10.1080/10739680600930222
Subject(s) - hypoxic pulmonary vasoconstriction , nadph oxidase , pulmonary hypertension , inward rectifier potassium ion channel , calcium in biology , voltage dependent calcium channel , depolarization , chemistry , microbiology and biotechnology , biology , reactive oxygen species , intracellular , vasoconstriction , medicine , calcium , endocrinology , biochemistry , ion channel , receptor
Potassium channels are tetrameric, membrane‐spanning proteins that selectively conduct K + at near diffusion‐limited rates. Their remarkable ionic selectivity results from a highly‐conserved K + recognition sequence in the pore. The classical function of K + channels is regulation of membrane potential ( E M ) and thence vascular tone. In pulmonary artery smooth muscle cells (PASMC), tonic K + egress, driven by a 145/5 mM intracellular/extracellular concentration gradient, contributes to a E M of about −60 mV. It has been recently discovered that K + channels also participate in vascular remodeling by regulating cell proliferation and apoptosis. PASMC express voltage‐gated (K v ), inward rectifier (K ir ), calcium‐sensitive (K Ca ), and two‐pore (K 2P ) channels. Certain K + channels are subject to rapid redox regulation by reactive oxygen species (ROS) derived from the PASMC's oxygen‐sensor (mitochondria and/or NADPH oxidase). Acute hypoxic inhibition of ROS production inhibits K v 1.5, which depolarizes E M , opens voltage‐sensitive, L‐type calcium channels, elevates cytosolic calcium, and initiates hypoxic pulmonary vasoconstriction (HPV). Hypoxia‐inhibited K + currents are not seen in systemic arterial SMCs. K v expression is also transcriptionally regulated by HIF‐1α and NFAT. Loss of PASMC K v 1.5 and K v 2.1 contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by causing a sustained depolarization, which increases intracellular calcium and K + , thereby stimulating cell proliferation and inhibiting apoptosis, respectively. Restoring K v expression (via K v 1.5 gene therapy, dichloroacetate, or anti‐survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous K v current (including an oxygen‐sensitive component), whereas conduit PASMC current is a K v /K Ca mosaic. This reflects regional differences in expression of channel isoforms, heterotetramers, splice variants, and regulatory subunits as well as mitochondrial diversity. In conclusion, K + channels regulate pulmonary vascular tone and remodeling and constitute potential therapeutic targets in the regression of PAH.