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; Philip Eaton

doi:10.1038/ncomms13187

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, Philip Eaton^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	13187
Number of pages	11
Journal	Nature Communications
Volume	7
Issue number	1
Early online date	26 Oct 2016
DOIs	https://doi.org/10.1038/ncomms13187
Publication status	Published - 26 Oct 2016

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Scotcher, J., Prysyazhna, O., Boguslavskyi, A., Kistamas, K., Hadgraft, N., Martin, E. D., Worthington, J., Rudyk, O., Rodriguez Cutillas, P., Cuello, F., Shattock, M. J., Marber, M. S., Conte, M. R., Greenstein, A., Greensmith, D. J., Venetucci, L., Timms, J. F., & Eaton, P. (2016). Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response. Nature Communications, 7(1), Article 13187. https://doi.org/10.1038/ncomms13187

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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.",

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

year = "2016",

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day = "26",

doi = "10.1038/ncomms13187",

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Scotcher, J , Prysyazhna, O , Boguslavskyi, A, Kistamas, K, Hadgraft, N, Martin, ED, Worthington, J, Rudyk, O, Rodriguez Cutillas, P, Cuello, F, Shattock, MJ , Marber, MS , Conte, MR, Greenstein, A, Greensmith, DJ, Venetucci, L, Timms, JF & Eaton, P 2016, 'Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response', Nature Communications, vol. 7, no. 1, 13187. https://doi.org/10.1038/ncomms13187

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T1 - Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response

AU - Scotcher, Jenna

AU - Prysyazhna, Oleksandra

AU - Boguslavskyi, Andrii

AU - Kistamas, Kornel

AU - Hadgraft, Natasha

AU - Martin, Eva D.

AU - Worthington, Jenny

AU - Rudyk, Olena

AU - Rodriguez Cutillas, Pedro

AU - Cuello, Friederike

AU - Shattock, Michael J.

AU - Marber, Michael S.

AU - Conte, Maria R.

AU - Greenstein, Adam

AU - Greensmith, David J.

AU - Venetucci, Luigi

AU - Timms, John F.

AU - Eaton, Philip

PY - 2016/10/26

Y1 - 2016/10/26

N2 - 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.

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

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