The LKB1–AMPK-α1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria
| Autor: | Marc Foretz, Sandy MacMillan, Benoit Viollet, Javier Moral-Sanz, D. Grahame Hardie, Carmel M. Moran, Sophronia A. Lewis, A. Mark Evans, Fiona A. Ross, Adrian Thomson |
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| Přispěvatelé: | Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), College of Life Sciences, University of Dundee |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MESH: Signal Transduction AMP-Activated Protein Kinases Mitochondrion Biochemistry MESH: Mice Knockout MESH: Hypoxia Hypoxic pulmonary vasoconstriction Myocyte MESH: Animals MESH: AMP-Activated Protein Kinases Hypoxia CAMKK2 Mice Knockout chemistry.chemical_classification MESH: Reactive Oxygen Species MESH: Myocytes Smooth Muscle [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Mitochondria 3. Good health Cell biology MESH: HEK293 Cells MESH: Vasoconstriction medicine.symptom Signal transduction Signal Transduction MESH: Mice Transgenic MESH: Mitochondria Myocytes Smooth Muscle MESH: Pulmonary Artery Mice Transgenic Protein Serine-Threonine Kinases Pulmonary Artery MESH: Protein-Serine-Threonine Kinases 03 medical and health sciences MESH: Mice Inbred C57BL medicine Animals Humans [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Molecular Biology Reactive oxygen species MESH: Humans AMPK [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Cell Biology Hypoxia (medical) Mice Inbred C57BL HEK293 Cells 030104 developmental biology chemistry Vasoconstriction Reactive Oxygen Species |
| Zdroj: | Science Signaling Science Signaling, American Association for the Advancement of Science, 2018, 11 (550), pp.eaau0296. ⟨10.1126/scisignal.aau0296⟩ Moral-Sanz, J, Lewis, S A, MacMillan, S, Ross, F A, Thomson, A, Viollet, B, Foretz, M, Moran, C, Hardie, D G & Evans, A M 2018, ' The LKB1-AMPK-α1 signalling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria ', Science Signaling, vol. 11, no. 550 . https://doi.org/10.1126/scisignal.aau0296 |
| ISSN: | 1937-9145 |
| DOI: | 10.1126/scisignal.aau0296⟩ |
| Popis: | International audience; Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Contrary to this model, we have shown that the LKB1-AMPK-α1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-α1 catalytic subunit blocked HPV in mice during mild (8% O2) and severe (5% O2) hypoxia, whereas AMPK-α2 deletion attenuated HPV only during severe hypoxia. By contrast, neither of these genetic manipulations affected serotonin-induced reductions in pulmonary vascular flow. HPV was also attenuated by reduced expression of LKB1, a kinase that activates AMPK during energy stress, but not after deletion of CaMKK2, a kinase that activates AMPK in response to increases in cytoplasmic Ca2+ Fluorescence imaging of acutely isolated pulmonary arterial myocytes revealed that AMPK-α1 or AMPK-α2 deletion did not affect mitochondrial membrane potential during normoxia or hypoxia. However, deletion of AMPK-α1, but not of AMPK-α2, blocked hypoxia from inhibiting KV1.5, the classical "oxygen-sensing" K+ channel in pulmonary arterial myocytes. We conclude that LKB1-AMPK-α1 signaling pathways downstream of mitochondria are critical for the induction of HPV, in a manner also supported by AMPK-α2 during severe hypoxia. |
| Databáze: | OpenAIRE |
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