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

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