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.
Highlights
Alveolar hypoxia induces contraction of pulmonary arteries, a phenomenon known as hypoxic pulmonary vasoconstriction (HPV), resulting in redistribution of blood from poorly to optimally ventilated lung segments
Since TASK-3 may compensate for the absence of TASK-1 [21, 22], we evaluated expression of TASK-3 mRNA along with TASK-1 mRNA in the heart, lung, and cerebellum of WT mice by Reverse Transcriptase (RT)-polymerase chain reaction (PCR)
We evaluated rise in pulmonary arterial pressure (PAP) in hypoxic ventilated lungs from WT and TASK-1 KO mice. 180 min of hypoxic ventilation resulted in a biphasic vasoconstrictory response; in the first phase, PAP reached a maximum within 10 min followed by a pressure nadir and a second increase starting after approximately 60 min of hypoxic ventilation
Summary
Alveolar hypoxia induces contraction of pulmonary arteries, a phenomenon known as hypoxic pulmonary vasoconstriction (HPV), resulting in redistribution of blood from poorly to optimally ventilated lung segments. The two-pore domain K+ channel, KCNK3 (potassium channel subfamily K member 3), known as TASK-1 (TWIK-related acid-sensitive K+ channel-1), has been implicated both in molecular mechanisms of HPV and in pathogenesis of PH. It is acid sensitive and inhibited by anandamide [2] and A293 [3]. Carotid body glomus cells show marked hypoxia-sensitive TASK activity [5, 6] which is absent in TASK-1 knockout (KO) mice [7, 8], and these mice show a marked reduction of the hypoxia-evoked increase in carotid sinus nerve discharge [9] These data point toward a contribution of TASK-1 in oxygen-dependent cellular signalling
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
