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 ORCID: https://orcid.org/0000-0002-6459-523X, Venetucci, L, Timms, JF and Eaton, P 2016, 'Disulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response' , Nature Communications, 7 , p. 13187.

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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.

Item Type:	Article
Schools:	Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title:	Nature Communications
Publisher:	Nature
ISSN:	2041-1723
Related URLs:	Publication
Funders:	British Heart Foundation, European Research Council (ERC Advanced award), Medical Research Council, Department of Health
Depositing User:	D Greensmith
Date Deposited:	02 Nov 2016 09:25
Last Modified:	15 Feb 2022 21:22
URI:	https://usir.salford.ac.uk/id/eprint/40525

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