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.
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 (EM) 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 EM 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 (Kv), inward rectifier (Kir), calcium-sensitive (KCa), and two-pore (K2P) 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 Kv1.5, which depolarizes EM, 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. Kv expression is also transcriptionally regulated by HIF-1alpha and NFAT. Loss of PASMC Kv1.5 and Kv2.1 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 Kv expression (via Kv1.5 gene therapy, dichloroacetate, or anti-survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous Kv current (including an oxygen-sensitive component), whereas conduit PASMC current is a Kv/KCa 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.
Moudgil
Rohit
R
Vascular Biology Group, Division of Cardiology, University of Alberta, Edmonton, Canada.
Michelakis
Evangelos D
ED
Archer
Stephen L
SL
D000818:Animals; D017209:Apoptosis; D020013:Calcium Signaling; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials; D010100:Oxygen / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014661:Vasoconstriction
D024642:Potassium Channels, Voltage-Gated; D017382:Reactive Oxygen Species; D010100:Oxygen