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

Jenna Scotcher, Oleksandra Prysyazhna, Andrii Boguslavskyi, Kornel Kistamas, Natasha Hadgraft, Eva D. Martin, Jenny Worthington, Olena Rudyk, Pedro Rodriguez Cutillas, Friederike Cuello, Michael J. Shattock, Michael S. Marber, Maria R. Conte, Adam Greenstein, David J. Greensmith, Luigi Venetucci, John F. Timms and Philip Eaton ()
Additional contact information
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

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13187

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