title: Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank-Starling response.
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.
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Jenna
authors: J
authors: Scotcher
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Oleksandra
authors: O
authors: Prysyazhna
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Andrii
authors: A
authors: Boguslavskyi
authors: Institute of Cardiovascular Sciences, Manchester Academic Health Science Centre, Core Technology Facility, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.
authors: Kornel
authors: K
authors: Kistamas
authors: Biomedical Research Centre, University of Salford, Peel Building, Salford Crescent M5 4WT, UK.
authors: Natasha
authors: N
authors: Hadgraft
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Eva D
authors: ED
authors: Martin
authors: Institute for Women's Health, University College London, Gower Street, London WC1E 6BT, UK.
authors: Jenny
authors: J
authors: Worthington
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Olena
authors: O
authors: Rudyk
authors: Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors: Pedro
authors: 0000-0002-3426-2274
authors: P
authors: Rodriguez Cutillas
authors: Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Centre, University Medical Center Hamburg-Eppendorf, Hamburg, DZHK (German Centre for Cardiovascular Research), Partner site Hamburg/Kiel/Lübeck, Hamburg 20246, Germany.
authors: Friederike
authors: F
authors: Cuello
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Michael J
authors: MJ
authors: Shattock
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Michael S
authors: MS
authors: Marber
authors: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.
authors: Maria R
authors: 0000-0001-8558-2051
authors: MR
authors: Conte
authors: Institute of Cardiovascular Sciences, Manchester Academic Health Science Centre, Core Technology Facility, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.
authors: Adam
authors: A
authors: Greenstein
authors: Biomedical Research Centre, University of Salford, Peel Building, Salford Crescent M5 4WT, UK.
authors: David J
authors: DJ
authors: Greensmith
authors: Institute of Cardiovascular Sciences, Manchester Academic Health Science Centre, Core Technology Facility, University of Manchester, 46 Grafton Street, Manchester M13 9NT, UK.
authors: Luigi
authors: L
authors: Venetucci
authors: Institute for Women's Health, University College London, Gower Street, London WC1E 6BT, UK.
authors: John F
authors: JF
authors: Timms
authors: King's College London, Cardiovascular Division, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK.
authors: Philip
authors: P
authors: Eaton
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002302:Cardiac Output / Q000502:physiology; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000235:genetics* / Q000378:metabolism; D003971:Diastole / Q000502:physiology*; D004220:Disulfides / Q000737:chemistry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006352:Heart Ventricles / Q000166:cytology / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology*; D009924:Organ Culture Techniques; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D061251:Primary Cell Culture; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D004220:Disulfides; D012694:Serine; D000099211:Phospholamban