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AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death

Author

Listed:
  • Javier Moral-Sanz

    (University of Edinburgh)

  • Sophronia A. Lewis

    (University of Edinburgh)

  • Sandy MacMillan

    (University of Edinburgh)

  • Marco Meloni

    (University of Edinburgh)

  • Heather McClafferty

    (University of Edinburgh)

  • Benoit Viollet

    (Université Paris Cité, CNRS, INSERM, Institut Cochin)

  • Marc Foretz

    (Université Paris Cité, CNRS, INSERM, Institut Cochin)

  • Jorge del-Pozo

    (University of Edinburgh Easter Bush Campus)

  • A. Mark Evans

    (University of Edinburgh)

Abstract

AMPK has been reported to facilitate hypoxic pulmonary vasoconstriction but, paradoxically, its deficiency precipitates pulmonary hypertension. Here we show that AMPK-α1/α2 deficiency in smooth muscles promotes persistent pulmonary hypertension of the new-born. Accordingly, dual AMPK-α1/α2 deletion in smooth muscles causes premature death of mice after birth, associated with increased muscularisation and remodeling throughout the pulmonary arterial tree, reduced alveolar numbers and alveolar membrane thickening, but with no oedema. Spectral Doppler ultrasound indicates pulmonary hypertension and attenuated hypoxic pulmonary vasoconstriction. Age-dependent right ventricular pressure elevation, dilation and reduced cardiac output was also evident. KV1.5 potassium currents of pulmonary arterial myocytes were markedly smaller under normoxia, which is known to facilitate pulmonary hypertension. Mitochondrial fragmentation and reactive oxygen species accumulation was also evident. Importantly, there was no evidence of systemic vasculopathy or hypertension in these mice. Moreover, hypoxic pulmonary vasoconstriction was attenuated by AMPK-α1 or AMPK-α2 deletion without triggering pulmonary hypertension.

Suggested Citation

  • Javier Moral-Sanz & Sophronia A. Lewis & Sandy MacMillan & Marco Meloni & Heather McClafferty & Benoit Viollet & Marc Foretz & Jorge del-Pozo & A. Mark Evans, 2022. "AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32568-7
    DOI: 10.1038/s41467-022-32568-7
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    1. Chen-Song Zhang & Simon A. Hawley & Yue Zong & Mengqi Li & Zhichao Wang & Alexander Gray & Teng Ma & Jiwen Cui & Jin-Wei Feng & Mingjiang Zhu & Yu-Qing Wu & Terytty Yang Li & Zhiyun Ye & Shu-Yong Lin , 2017. "Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK," Nature, Nature, vol. 548(7665), pages 112-116, August.
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