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

被引：0
作者：
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
Philip Eaton
机构：
[1] King’s College London,Cardiovascular Division
[2] The British Heart Foundation Centre of Excellence,Department of Experimental Pharmacology and Toxicology
[3] The Rayne Institute,Randall Division of Cell and Molecular Biophysics
[4] St Thomas’ Hospital,undefined
[5] Institute of Cardiovascular Sciences,undefined
[6] Manchester Academic Health Science Centre,undefined
[7] Core Technology Facility,undefined
[8] University of Manchester,undefined
[9] Biomedical Research Centre,undefined
[10] University of Salford,undefined
[11] Peel Building,undefined
[12] Institute for Women’s Health,undefined
[13] University College London,undefined
[14] Barts Cancer Institute,undefined
[15] Barts and The London School of Medicine and Dentistry,undefined
[16] Queen Mary University of London,undefined
[17] Charterhouse Square,undefined
[18] Cardiovascular Research Centre,undefined
[19] University Medical Center Hamburg-Eppendorf,undefined
[20] Hamburg,undefined
[21] DZHK (German Centre for Cardiovascular Research),undefined
[22] Partner site Hamburg/Kiel/Lübeck,undefined
[23] King’s College London,undefined
[24] New Hunt’s House,undefined
[25] Guy’s Campus,undefined
来源：
Nature Communications | / 7卷
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摘要：
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.
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