Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species.
There is current discussion whether reactive oxygen species are up- or downregulated in the pulmonary circulation during hypoxia, from which sources (i.e., mitochondria or NADPH oxidases) they are derived, and what the downstream targets of ROS are. We recently showed that the NADPH oxidase homolog NOX4 is upregulated in hypoxia-induced pulmonary hypertension in mice and contributes to the vascular remodeling in pulmonary hypertension. We here tested the hypothesis that NOX4 regulates K(v) channels via an increased ROS formation after prolonged hypoxia. We showed that (1) NOX4 is upregulated in hypoxia-induced pulmonary hypertension in rats and isolated rat pulmonary arterial smooth muscle cells (PASMC) after 3days of hypoxia, and (2) that NOX4 is a major contributor to increased reactive oxygen species (ROS) after hypoxia. Our data indicate colocalization of K(v)1.5 and NOX4 in isolated PASMC. The NADPH oxidase inhibitor and ROS scavenger apocynin as well as NOX4 siRNA reversed the hypoxia-induced decrease in K(v) current density whereas the protein levels of the channels remain unaffected by siNOX4 treatment. Determination of cysteine oxidation revealed increased NOX4-mediated K(v)1.5 channel oxidation. We conclude that sustained hypoxia decreases K(v) channel currents by a direct effect of a NOX4-derived increase in ROS.
Excellence Cluster Cardio-Pulmonary System, University of Giessen Lung Center, Justus-Liebig-University, Medical Clinic II/V, Aulweg 130, Giessen 35392, Germany.
Manish
M
Mittal
Xiang Q
XQ
Gu
Oleg
O
Pak
Matthew E
ME
Pamenter
Daniela
D
Haag
D Beate
DB
Fuchs
Ralph T
RT
Schermuly
H A
HA
Ghofrani
Ralf P
RP
Brandes
Werner
W
Seeger
Friedrich
F
Grimminger
Gabriel G
GG
Haddad
Norbert
N
Weissmann
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D051666:Kv1.5 Potassium Channel / Q000378:metabolism*; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D021381:Protein Transport; D011651:Pulmonary Artery / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D000098:Acetophenones; D051666:Kv1.5 Potassium Channel; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C056165:acetovanillone; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat