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

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

Authors

J Scotcher

O Prysyazhna

A Boguslavskyi

K Kistamas

N Hadgraft

ED Martin

J Worthington

O Rudyk

P Rodriguez Cutillas

F Cuello

MJ Shattock

MS Marber

MR Conte

A Greenstein

L Venetucci

JF Timms

P Eaton



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.

Citation

Scotcher, J., Prysyazhna, O., Boguslavskyi, A., Kistamas, K., Hadgraft, N., Martin, E., …Eaton, P. (2016). Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response. Nature communications, 7, 13187. https://doi.org/10.1038/ncomms13187

Journal Article Type Article
Acceptance Date Sep 9, 2016
Online Publication Date Oct 26, 2016
Publication Date Oct 26, 2016
Deposit Date Nov 2, 2016
Publicly Available Date Nov 2, 2016
Journal Nature Communications
Print ISSN 2041-1723
Volume 7
Pages 13187
DOI https://doi.org/10.1038/ncomms13187
Publisher URL http://dx.doi.org/10.1038/ncomms13187
Related Public URLs http://www.nature.com/articles/ncomms13187

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