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      Diabetic Hyperglycemia activates CaMKII and Arrhythmias by O linked Glycosylation

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          Summary

          Ca 2+-Calmodulin dependent protein kinase II (CaMKII) is a regulatory node in heart and brain, and its chronic activation can be pathological. CaMKII activation seen in heart failure can directly induce pathological changes in ion channels, Ca 2+ handling and gene transcription. 1 Here we discover a novel mechanism linking CaMKII and hyperglycemic signaling in diabetes mellitus, which is a key risk factor for heart 2 and neurodegenerative diseases. 3, 4 Acute hyperglycemia 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+] declines. O-GlcNAc modified CaMKII is increased in heart and brain from diabetic humans and rats. In cardiomyocytes, increased [glucose] significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum (SR) Ca 2+ release events that can contribute to cardiac mechanical dysfunction and arrhythmias. 1 These effects were prevented by pharmacological inhibition of O-GlcNAc signaling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were enhanced by increased [glucose] via 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 signaling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.

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          Most cited references27

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          Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic beta-N-acetylglucosaminidase from human brain.

          Dynamic modification of cytoplasmic and nuclear proteins by O-linked N-acetylglucosamine (O-GlcNAc) on Ser/Thr residues is ubiquitous in higher eukaryotes and is analogous to protein phosphorylation. The enzyme for the addition of this modification, O-GlcNAc transferase, has been cloned from several species. Here, we have cloned a human brain O-GlcNAcase that cleaves O-GlcNAc off proteins. The cloned cDNA encodes a polypeptide of 916 amino acids with a predicted molecular mass of 103 kDa and a pI value of 4.63, but the protein migrates as a 130-kDa band on SDS-polyacrylamide gel electrophoresis. The cloned O-GlcNAcase has a pH optimum of 5.5-7.0 and is inhibited by GlcNAc but not by GalNAc. p-Nitrophenyl (pNP)-beta-GlcNAc, but not pNP-beta-GalNAc or pNP-alpha-GlcNAc, is a substrate. The cloned enzyme cleaves GlcNAc, but not GalNAc, from glycopeptides. Cell fractionation suggests that the overexpressed protein is mostly localized in the cytoplasm. It therefore has all the expected characteristics of O-GlcNAcase and is distinct from lysosomal hexosaminidases. Northern blots show that the transcript is expressed in every human tissue examined but is the highest in the brain, placenta, and pancreas. An understanding of O-GlcNAc dynamics and O-GlcNAcase may be key to elucidating the relationships between O-phosphate and O-GlcNAc and to the understanding of the molecular mechanisms of diseases such as diabetes, cancer, and neurodegeneration.
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            CaMKII in myocardial hypertrophy and heart failure.

            Many signals have risen and fallen in the tide of investigation into mechanisms of myocardial hypertrophy and heart failure (HF). In our opinion, the multifunctional Ca and calmodulin-dependent protein kinase II (CaMKII) has emerged as a molecule to watch, in part because a solid body of accumulated data essentially satisfy Koch's postulates, showing that the CaMKII pathway is a core mechanism for promoting myocardial hypertrophy and heart failure. Multiple groups have now confirmed the following: (1) that CaMKII activity is increased in hypertrophied and failing myocardium from animal models and patients; (2) CaMKII overexpression causes myocardial hypertrophy and HF and (3) CaMKII inhibition (by drugs, inhibitory peptides and gene deletion) improves myocardial hypertrophy and HF. Patients with myocardial disease die in equal proportion from HF and arrhythmias, and a major therapeutic obstacle is that drugs designed to enhance myocardial contraction promote arrhythmias. In contrast, inhibiting the CaMKII pathway appears to reduce arrhythmias and improve myocardial responses to pathological stimuli. This brief paper will introduce the molecular physiology of CaMKII and discuss the impact of CaMKII on ion channels, Ca handling proteins and transcription in myocardium. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure". Copyright © 2011 Elsevier Ltd. All rights reserved.
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              The deltaC isoform of CaMKII is activated in cardiac hypertrophy and induces dilated cardiomyopathy and heart failure.

              Recent studies have demonstrated that transgenic (TG) expression of either Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) or CaMKIIdeltaB, both of which localize to the nucleus, induces cardiac hypertrophy. However, CaMKIV is not present in heart, and cardiomyocytes express not only the nuclear CaMKIIdeltaB but also a cytoplasmic isoform, CaMKIIdeltaC. In the present study, we demonstrate that expression of the deltaC isoform of CaMKII is selectively increased and its phosphorylation elevated as early as 2 days and continuously for up to 7 days after pressure overload. To determine whether enhanced activity of this cytoplasmic deltaC isoform of CaMKII can lead to phosphorylation of Ca2+ regulatory proteins and induce hypertrophy, we generated TG mice that expressed the deltaC isoform of CaMKII. Immunocytochemical staining demonstrated that the expressed transgene is confined to the cytoplasm of cardiomyocytes isolated from these mice. These mice develop a dilated cardiomyopathy with up to a 65% decrease in fractional shortening and die prematurely. Isolated myocytes are enlarged and exhibit reduced contractility and altered Ca2+ handling. Phosphorylation of the ryanodine receptor (RyR) at a CaMKII site is increased even before development of heart failure, and CaMKII is found associated with the RyR in immunoprecipitates from the CaMKII TG mice. Phosphorylation of phospholamban is also increased specifically at the CaMKII but not at the PKA phosphorylation site. These findings are the first to demonstrate that CaMKIIdeltaC can mediate phosphorylation of Ca2+ regulatory proteins in vivo and provide evidence for the involvement of CaMKIIdeltaC activation in the pathogenesis of dilated cardiomyopathy and heart failure.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                28 August 2013
                29 September 2013
                17 October 2013
                17 April 2014
                : 502
                : 7471
                : 372-376
                Affiliations
                [1 ]Department of Pharmacology, University of California, Davis, 451 Health Sciences Drive, Davis, CA 95616
                [2 ]Department of Physiology, University of Otago, Dunedin 9054, New Zealand
                [3 ]Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205
                [4 ]Department of Molecular and Biomedical Pharmacology, University of Kentucky, 900 S. Limestone, Lexington, KY 40536
                Author notes
                []Correspondence to: Donald M. Bers, Ph.D., Department of Pharmacology, University of California, Davis, Genome Building Rm 3513, Davis, CA 95616-8636, Phone: 530-752-6517, Fax: 530-752-7710, dmbers@ 123456ucdavis.edu
                Article
                NIHMS515163
                10.1038/nature12537
                3801227
                24077098
                804a9678-fbb6-4d85-896e-6552dff93c94

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                History
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: T32 HL086350 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL111600 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R01 HL030077 || HL
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases : NIDDK
                Award ID: R01 DK061671 || DK
                Funded by: National Institute on Aging : NIA
                Award ID: P30 AG010129 || AG
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL107153 || HL
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: P01 HL080101 || HL
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