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.
Highlights
USIR is a digital collection of the research output of the University of Salford
We find that hearts of Cys42Ser protein kinase G Ia (PKGIa) knock-in (KI) mice, which are resistant to PKGIa oxidation, have diastolic dysfunction and a diminished ability to couple ventricular filling with cardiac output on a beat-to-beat basis
Substrate phosphorylation was assessed when PKGIa was activated by the Cys[42] disulfide bond or via the classical pathway with cyclic guanosine monophosphate (cGMP), and compared with phosphorylation when PKGIa was in its basal ‘unactivated’ state
Summary
USIR is a digital collection of the research output of the University of Salford. Where copyright permits, full text material held in the repository is made freely available online and can be read, downloaded and copied for non-commercial private study or research purposes. 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 and Eaton, P
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