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Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation

2013; Nature Portfolio; Volume: 502; Issue: 7471 Linguagem: Inglês

10.1038/nature12537

1476-4687

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

Cardiac electrophysiology and arrhythmias

CaMKII is known to be pathologically activated in heart failure and arrhythmias; here it is shown that glucose-induced CaMKII activation via O-linked glycosylation might contribute to cardiac pathology in diabetes. During heart failure the enzyme Ca2+/calmodulin-dependent protein kinase II (CaMKII) becomes autonomously activated, potentially disrupting ion-channel gating and calcium handling. This paper suggests that glucose-induced CaMKII activation might contribute to cardiac pathology in diabetes. The authors show that high glucose induces covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc) at a specific residue. This activates CaMKII and enhances spontaneous calcium release events that can contribute to arrhythmias. Increased levels of O-GlcNAc-modified CaMKII were found in the hearts and brains of diabetic patients and in rats. In addition, signs of arrhythmia in isolated perfused rat hearts were prevented by CaMKII inactivation or by blocking O-GlcNAc modification. 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, Ca2+ handling and gene transcription1. 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 heart2 and neurodegenerative diseases3,4. 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 Ca2+ 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 arrhythmias1. 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.