| First Author | Moral-Sanz J | Year | 2018 |
| Journal | Sci Signal | Volume | 11 |
| Issue | 550 | PubMed ID | 30279167 |
| Mgi Jnum | J:281798 | Mgi Id | MGI:6380781 |
| Doi | 10.1126/scisignal.aau0296 | Citation | Moral-Sanz J, et al. (2018) The LKB1-AMPK-alpha1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria. Sci Signal 11(550) |
| abstractText | 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-alpha1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-alpha1 catalytic subunit blocked HPV in mice during mild (8% O2) and severe (5% O2) hypoxia, whereas AMPK-alpha2 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 Ca(2+) Fluorescence imaging of acutely isolated pulmonary arterial myocytes revealed that AMPK-alpha1 or AMPK-alpha2 deletion did not affect mitochondrial membrane potential during normoxia or hypoxia. However, deletion of AMPK-alpha1, but not of AMPK-alpha2, blocked hypoxia from inhibiting KV1.5, the classical "oxygen-sensing" K(+) channel in pulmonary arterial myocytes. We conclude that LKB1-AMPK-alpha1 signaling pathways downstream of mitochondria are critical for the induction of HPV, in a manner also supported by AMPK-alpha2 during severe hypoxia. |
