Role of RyR2 phosphorylation at S2814 during heart failure progression

Jonathan L. Respress, Ralph J. Van Oort, Na Li, Natale Rolim, Sayali S. Dixit, Angela Dealmeida, Niels Voigt, William S. Lawrence, Darlene G. Skapura, Kristine Skårdal, Ulrik Wisløff, Thomas Wieland, Xun Ai, Steven M. Pogwizd, Dobromir Dobrev, Xander H.T. Wehrens

Research output: Contribution to journalArticle

133 Scopus citations

Abstract

Rationale: Increased activity of Ca/calmodulin-dependent protein kinase II (CaMKII) is thought to promote heart failure (HF) progression. However, the importance of CaMKII phosphorylation of ryanodine receptors (RyR2) in HF development and associated diastolic sarcoplasmic reticulum Ca leak is unclear. Objective: Determine the role of CaMKII phosphorylation of RyR2 in patients and mice with nonischemic and ischemic forms of HF. Methods and Results: Phosphorylation of the primary CaMKII site S2814 on RyR2 was increased in patients with nonischemic, but not with ischemic, HF. Knock-in mice with an inactivated S2814 phosphorylation site were relatively protected from HF development after transverse aortic constriction compared with wild-type littermates. After transverse aortic constriction, S2814A mice did not exhibit pulmonary congestion and had reduced levels of atrial natriuretic factor. Cardiomyocytes from S2814A mice exhibited significantly lower sarcoplasmic reticulum Ca leak and improved sarcoplasmic reticulum Ca loading compared with wild-type mice after transverse aortic constriction. Interestingly, these protective effects on cardiac contractility were not observed in S2814A mice after experimental myocardial infarction. Conclusions: Our results suggest that increased CaMKII phosphorylation of RyR2 plays a role in the development of pathological sarcoplasmic reticulum Ca leak and HF development in nonischemic forms of HF such as transverse aortic constriction in mice.

Original languageEnglish (US)
Pages (from-to)1474-1483
Number of pages10
JournalCirculation Research
Volume110
Issue number11
DOIs
StatePublished - May 25 2012

Keywords

  • calcium
  • heart failure
  • ryanodine receptor
  • sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Respress, J. L., Van Oort, R. J., Li, N., Rolim, N., Dixit, S. S., Dealmeida, A., Voigt, N., Lawrence, W. S., Skapura, D. G., Skårdal, K., Wisløff, U., Wieland, T., Ai, X., Pogwizd, S. M., Dobrev, D., & Wehrens, X. H. T. (2012). Role of RyR2 phosphorylation at S2814 during heart failure progression. Circulation Research, 110(11), 1474-1483. https://doi.org/10.1161/CIRCRESAHA.112.268094