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  • 1
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    Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-10-01
    Description: Ca(2+)/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 Ca(2+) 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 CaMKIIdelta. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801227/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3801227/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Erickson, Jeffrey R -- Pereira, Laetitia -- Wang, Lianguo -- Han, Guanghui -- Ferguson, Amanda -- Dao, Khanha -- Copeland, Ronald J -- Despa, Florin -- Hart, Gerald W -- Ripplinger, Crystal M -- Bers, Donald M -- 1R01HL118474-01A1/HL/NHLBI NIH HHS/ -- P01 HL080101/HL/NHLBI NIH HHS/ -- P01 HL107153/HL/NHLBI NIH HHS/ -- P01HL080101/HL/NHLBI NIH HHS/ -- P01HL107153/HL/NHLBI NIH HHS/ -- P30 AG010129/AG/NIA NIH HHS/ -- P30AG010129/AG/NIA NIH HHS/ -- R01 DK061671/DK/NIDDK NIH HHS/ -- R01 HL030077/HL/NHLBI NIH HHS/ -- R01 HL105242/HL/NHLBI NIH HHS/ -- R01 HL111600/HL/NHLBI NIH HHS/ -- R01 HL118474/HL/NHLBI NIH HHS/ -- R01DK61671/DK/NIDDK NIH HHS/ -- R01HL111600/HL/NHLBI NIH HHS/ -- R37 HL030077/HL/NHLBI NIH HHS/ -- R37HL30077/HL/NHLBI NIH HHS/ -- T32 HL086350/HL/NHLBI NIH HHS/ -- T32HL86350/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Oct 17;502(7471):372-6. doi: 10.1038/nature12537. Epub 2013 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of California, Davis, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24077098" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/metabolism ; Animals ; Arrhythmias, Cardiac/complications/enzymology/*metabolism ; Benzylamines/pharmacology ; Brain/drug effects/enzymology ; Calcium/metabolism ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Diabetes Complications/enzymology/*metabolism ; Diazooxonorleucine/pharmacology ; Enzyme Activation/drug effects ; Glucose/metabolism/pharmacology ; Glycosylation/drug effects ; Humans ; Hyperglycemia/complications/enzymology/*metabolism ; Mice ; Myocardium/cytology/enzymology ; Myocytes, Cardiac/enzymology/metabolism ; Rats ; Sarcoplasmic Reticulum/metabolism ; Sulfonamides/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    LabHEART: an interactive computer model of rabbit ventricular myocyte ion channels and Ca transport (2001)
    In:  Other Sources
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    Publication Date: 2019-07-13
    Description: An interactive computer program, LabHEART, was developed to simulate the action potential (AP), ionic currents, and Ca handling mechanisms in a rabbit ventricular myocyte. User-oriented, its design allows switching between voltage and current clamp and easy on-line manipulation of key parameters to change the original formulation. The model reproduces normal rabbit ventricular myocyte currents, Ca transients, and APs. We also changed parameters to simulate data from heart failure (HF) myocytes, including reduced transient outward (I(to)) and inward rectifying K currents (I(K1)), enhanced Na/Ca exchange expression, and reduced sarcoplasmic reticulum Ca-ATPase function, but unaltered Ca current density. These changes caused reduced Ca transient amplitude and increased AP duration (especially at lower frequency) as observed experimentally. The model shows that the increased Na/Ca exchange current (I(NaCa)) in HF lowers the intracellular [Ca] threshold for a triggered AP from 800 to 540 nM. Similarly, the decrease in I(K1) reduces the threshold to 600 nM. Changes in I(to) have no effect. Combining enhanced Na/Ca exchange with reduced I(K1) (as in HF) lowers the threshold to trigger an AP to 380 nM. These changes reproduce experimental results in HF, where the contributions of different factors are not readily distinguishable. We conclude that the triggered APs that contribute to nonreentrant ventricular tachycardia in HF are due approximately equally (and nearly additively) to alterations in I(NaCa) and I(K1). A free copy of this software can be obtained at http://www.meddean.luc.edu/lumen/DeptWebs/physio/bers.html.
    Keywords: Life Sciences (General)
    Type: American journal of physiology. Cell physiology (ISSN 0363-6143); 281; 6; C2049-60
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  • 3
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    Ising model of cardiac thin filament activation with nearest-neighbor cooperative interactions (2003)
    In:  Other Sources
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    Publication Date: 2019-07-13
    Description: We have developed a model of cardiac thin filament activation using an Ising model approach from equilibrium statistical physics. This model explicitly represents nearest-neighbor interactions between 26 troponin/tropomyosin units along a one-dimensional array that represents the cardiac thin filament. With transition rates chosen to match experimental data, the results show that the resulting force-pCa (F-pCa) relations are similar to Hill functions with asymmetries, as seen in experimental data. Specifically, Hill plots showing (log(F/(1-F)) vs. log [Ca]) reveal a steeper slope below the half activation point (Ca(50)) compared with above. Parameter variation studies show interplay of parameters that affect the apparent cooperativity and asymmetry in the F-pCa relations. The model also predicts that Ca binding is uncooperative for low [Ca], becomes steeper near Ca(50), and becomes uncooperative again at higher [Ca]. The steepness near Ca(50) mirrors the steep F-pCa as a result of thermodynamic considerations. The model also predicts that the correlation between troponin/tropomyosin units along the one-dimensional array quickly decays at high and low [Ca], but near Ca(50), high correlation occurs across the whole array. This work provides a simple model that can account for the steepness and shape of F-pCa relations that other models fail to reproduce.
    Keywords: Life Sciences (General)
    Type: Biophysical journal (ISSN 0006-3495); 84; 2 Pt 1; 897-909
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  • 4
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    Cardiac myofilaments: mechanics and regulation (2003)
    In:  Other Sources
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    Publication Date: 2019-07-13
    Description: The mechanical properties of the cardiac myofilament are an important determinant of pump function of the heart. This report is focused on the regulation of myofilament function in cardiac muscle. Calcium ions form the trigger that induces activation of the thin filament which, in turn, allows for cross-bridge formation, ATP hydrolysis, and force development. The structure and protein-protein interactions of the cardiac sarcomere that are responsible for these processes will be reviewed. The molecular mechanism that underlies myofilament activation is incompletely understood. Recent experimental approaches have been employed to unravel the mechanism and regulation of myofilament mechanics and energetics by activator calcium and sarcomere length, as well as contractile protein phosphorylation mediated by protein kinase A. Central to these studies is the question whether such factors impact on muscle function simply by altering thin filament activation state, or whether modulation of cross-bridge cycling also plays a part in the responses of muscle to these stimuli.
    Keywords: Life Sciences (General)
    Type: Journal of biomechanics (ISSN 0021-9290); 36; 5; 721-30
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  • 5
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    Frank-Starling law of the heart and the cellular mechanisms of length-dependent activation (2002)
    In:  Other Sources
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    Publication Date: 2019-07-13
    Description: No abstract available
    Keywords: Life Sciences (General)
    Type: Pflugers Archiv : European journal of physiology (ISSN 0031-6768); 445; 3; 305-10
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