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Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response

Author

Listed:
  • Jenna Scotcher

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

  • Oleksandra Prysyazhna

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

  • Andrii Boguslavskyi

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

  • Kornel Kistamas

    (Institute of Cardiovascular Sciences, Manchester Academic Health Science Centre, Core Technology Facility, University of Manchester)

  • Natasha Hadgraft

    (Biomedical Research Centre, University of Salford, Peel Building)

  • Eva D. Martin

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

  • Jenny Worthington

    (Institute for Women’s Health, University College London)

  • Olena Rudyk

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

  • Pedro Rodriguez Cutillas

    (Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square)

  • Friederike Cuello

    (Cardiovascular Research Centre, University Medical Center Hamburg-Eppendorf, Hamburg, DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck)

  • Michael J. Shattock

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

  • Michael S. Marber

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

  • Maria R. Conte

    (King’s College London, New Hunt’s House, Guy’s Campus)

  • Adam Greenstein

    (Institute of Cardiovascular Sciences, Manchester Academic Health Science Centre, Core Technology Facility, University of Manchester)

  • David J. Greensmith

    (Biomedical Research Centre, University of Salford, Peel Building)

  • Luigi Venetucci

    (Institute of Cardiovascular Sciences, Manchester Academic Health Science Centre, Core Technology Facility, University of Manchester)

  • John F. Timms

    (Institute for Women’s Health, University College London)

  • Philip Eaton

    (King’s College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas’ Hospital)

Abstract

The Frank–Starling mechanism allows the amount of blood entering the heart from the veins to be precisely matched with the amount pumped out to the arterial circulation. As the heart fills with blood during diastole, the myocardium is stretched and oxidants are produced. Here we show that protein kinase G Iα (PKGIα) is oxidant-activated during stretch and this form of the kinase selectively phosphorylates cardiac phospholamban Ser16—a site important for diastolic relaxation. We find that hearts of Cys42Ser PKGIα knock-in (KI) mice, which are resistant to PKGIα oxidation, have diastolic dysfunction and a diminished ability to couple ventricular filling with cardiac output on a beat-to-beat basis. Intracellular calcium dynamics of ventricular myocytes isolated from KI hearts are altered in a manner consistent with impaired relaxation and contractile function. We conclude that oxidation of PKGIα during myocardial stretch is crucial for diastolic relaxation and fine-tunes the Frank–Starling response.

Suggested Citation

  • Jenna Scotcher & Oleksandra Prysyazhna & Andrii Boguslavskyi & Kornel Kistamas & Natasha Hadgraft & Eva D. Martin & Jenny Worthington & Olena Rudyk & Pedro Rodriguez Cutillas & Friederike Cuello & Mic, 2016. "Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response," Nature Communications, Nature, vol. 7(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13187
    DOI: 10.1038/ncomms13187
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