title: TASK-1 potassium channel is not critically involved in mediating hypoxic pulmonary vasoconstriction of murine intra-pulmonary arteries.
abstract: The two-pore domain potassium channel KCNK3 (TASK-1) is expressed in rat and human pulmonary artery smooth muscle cells. There, it is associated with hypoxia-induced signalling, and its dysfunction is linked to pathogenesis of human pulmonary hypertension. We here aimed to determine its role in hypoxic pulmonary vasoconstriction (HPV) in the mouse, and hence the suitability of this model for further mechanistic investigations, using appropriate inhibitors and TASK-1 knockout (KO) mice. RT-PCR revealed expression of TASK-1 mRNA in murine lungs and pre-acinar pulmonary arteries. Protein localization by immunohistochemistry and western blot was unreliable since all antibodies produced labelling also in TASK-1 KO organs/tissues. HPV was investigated by videomorphometric analysis of intra- (inner diameter: 25-40 μm) and pre-acinar pulmonary arteries (inner diameter: 41-60 μm). HPV persisted in TASK-1 KO intra-acinar arteries. Pre-acinar arteries developed initial HPV, but the response faded earlier (after 30 min) in KO vessels. This HPV pattern was grossly mimicked by the TASK-1 inhibitor anandamide in wild-type vessels. Hypoxia-provoked rise in pulmonary arterial pressure (PAP) in isolated ventilated lungs was affected neither by TASK-1 gene deficiency nor by the TASK-1 inhibitor A293. TASK-1 is dispensable for initiating HPV of murine intra-pulmonary arteries, but participates in sustained HPV specifically in pre-acinar arteries. This does not translate into abnormal rise in PAP. While there is compelling evidence that TASK-1 is involved in the pathogenesis of pulmonary arterial hypertension in humans, the mouse does not appear to serve as a suitable model to study the underlying molecular mechanisms.
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Ghulam
authors.initials: G
authors.lastname: Murtaza
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Mermer
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Goldenberg
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Pfeil
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.
authors.forename: Renate
authors.initials: R
authors.lastname: Paddenberg
authors.affiliation: Universities of Giessen and Marburg Lung Center, Justus-Liebig-University, Giessen, Germany.|German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Justus-Liebig-University, Giessen, Germany.
authors.forename: Nobert
authors.initials: N
authors.lastname: Weissmann
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Justus-Liebig University, Giessen, Germany.
authors.forename: Guenter
authors.initials: G
authors.lastname: Lochnit
authors.affiliation: Institute of Anatomy and Cell Biology, Justus-Liebig-University, Giessen, Germany.|German Center for Lung Research, Excellence Cluster Cardio-Pulmonary System, Justus-Liebig-University, Giessen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D063388:Endocannabinoids / Q000494:pharmacology; D005260:Female; D000860:Hypoxia / Q000503:physiopathology*; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000502:physiology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D009419:Nerve Tissue Proteins; D053284:Polyunsaturated Alkamides; D024683:Potassium Channels, Tandem Pore Domain; D012333:RNA, Messenger; C420132:potassium channel subfamily K member 3; C078814:anandamide