Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation

Jeffrey R. Erickson, Laetitia Pereira, Lianguo Wang, Guanghui Han, Amanda Ferguson, Khanha Dao, Ronald J. Copeland, Florin Despa, Gerald W. Hart, Crystal M. Ripplinger, Donald M. Bers

Research output: Contribution to journalArticlepeer-review

399 Scopus citations

Abstract

Ca2+ /calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca 2+ handling and gene transcription. Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart and neurodegenerative diseases. Acute hyperglycaemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII autonomously, creating molecular memory even after Ca 2+ concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum Ca2+ release events that can contribute to cardiac mechanical dysfunction and arrhythmias. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.

Original languageEnglish
Pages (from-to)372-376
Number of pages5
JournalNature
Volume502
Issue number7471
DOIs
StatePublished - 2013

Bibliographical note

Funding Information:
Acknowledgements We thank Y. Hayashi for providing initial Camui samples, H. Schulman for helpful discussions, K. Margulies for human heart samples, L.-W. Jin, M. Melara and the University of California, Davis Alzheimer’s Disease Center (NIH-P30AG010129) for human brain samples, and J. H. Brown for providing CaMKIId-knockout mice. We thank Pfizer, Inc. for the gift of a breeding pair of HIP rats to F.D. This work was supported by American Heart Association 13SDG14680072 and National Institutes of Health (NIH) T32HL86350 (J.R.E.); NIH 1R01HL118474-01A1, NSF CBET 1133339, ADA 1-13-IN-70 and AHA 13GRNT16470034 (F.D.); NIH R01DK61671 and P01HL107153 (G.W.H.); NIH R01HL111600 (C.M.R.); NIH P01HL080101, R37HL30077 and Fondation Leducq Transatlantic CaMKII Alliance (D.M.B.). G.W.H. receives a share of royalty on sales of the CTD 110.6 antibody, which are managed by Johns Hopkins University.

ASJC Scopus subject areas

  • General

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