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

• Published in: Nature communications 2016-10, Vol.7 (1), p.13187-11, Article 13187
• Main Authors: Scotcher, Jenna, Prysyazhna, Oleksandra, Boguslavskyi, Andrii, Kistamas, Kornel, Hadgraft, Natasha, Martin, Eva D., Worthington, Jenny, Rudyk, Olena, Rodriguez Cutillas, Pedro, Cuello, Friederike, Shattock, Michael J., Marber, Michael S., Conte, Maria R., Greenstein, Adam, Greensmith, David J., Venetucci, Luigi, Timms, John F., Eaton, Philip
• Format: Article
• Language: English
• Subjects: 13; 13/1; 631/443/592; 64/110; 692/4019/592; 82; 82/29; 82/83; Animals; Biomechanical Phenomena; Calcium - metabolism; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cardiac Output - physiology; Cyclic GMP-Dependent Protein Kinase Type I - genetics; Cyclic GMP-Dependent Protein Kinase Type I - metabolism; Diastole - physiology; Disulfides - chemistry; Gene Expression Profiling; Gene Expression Regulation; Gene Knock-In Techniques; Heart Ventricles - cytology; Heart Ventricles - enzymology; Humanities and Social Sciences; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Myocardial Contraction - physiology; Myocardium - cytology; Myocardium - enzymology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - enzymology; Organ Culture Techniques; Oxidation-Reduction; Oxidative Stress; Phosphorylation; Primary Cell Culture; Science; Science (multidisciplinary); Serine - metabolism; Substrate Specificity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13187

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. The stroke volume of the heart increases in response to an increase in the blood volume filling the heart. Here the authors reveal that this coordinated process is mediated in part by oxidative activation of the protein kinase G Iα, which phosphorylates phospholamban to enhance diastolic relaxation in mice.