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CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia

RATIONALE: Diabetic hyperglycemia is associated with cardiac dysfunction and increased arrhythmia risk, and CaMKII (calcium/calmodulin-dependent protein kinase II) function has been implicated. CaMKII activity is promoted by both oxidation and O-linked β-N-acetylglucosamine (O-GlcNAc) of known CaMKI...

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Autores principales: Hegyi, Bence, Fasoli, Anna, Ko, Christopher Y., Van, Benjamin W., Alim, Chidera C., Shen, Erin Y., Ciccozzi, Marisa M., Tapa, Srinivas, Ripplinger, Crystal M., Erickson, Jeffrey R., Bossuyt, Julie, Bers, Donald M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221539/
https://www.ncbi.nlm.nih.gov/pubmed/33926209
http://dx.doi.org/10.1161/CIRCRESAHA.120.318402
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author Hegyi, Bence
Fasoli, Anna
Ko, Christopher Y.
Van, Benjamin W.
Alim, Chidera C.
Shen, Erin Y.
Ciccozzi, Marisa M.
Tapa, Srinivas
Ripplinger, Crystal M.
Erickson, Jeffrey R.
Bossuyt, Julie
Bers, Donald M.
author_facet Hegyi, Bence
Fasoli, Anna
Ko, Christopher Y.
Van, Benjamin W.
Alim, Chidera C.
Shen, Erin Y.
Ciccozzi, Marisa M.
Tapa, Srinivas
Ripplinger, Crystal M.
Erickson, Jeffrey R.
Bossuyt, Julie
Bers, Donald M.
author_sort Hegyi, Bence
collection PubMed
description RATIONALE: Diabetic hyperglycemia is associated with cardiac dysfunction and increased arrhythmia risk, and CaMKII (calcium/calmodulin-dependent protein kinase II) function has been implicated. CaMKII activity is promoted by both oxidation and O-linked β-N-acetylglucosamine (O-GlcNAc) of known CaMKII sites. OBJECTIVE: To investigate which posttranslational modifications occur in human diabetic hearts and how they alter electrophysiological and Ca(2+) handling properties in hyperglycemia. METHODS AND RESULTS: We assessed echocardiography, electrophysiology, Ca(2+)-handling, and protein expression in site-specific CaMKII mutant mice (O-GlcNAc-resistant S280A and oxidation-resistant MM281/2VV knock-ins, and global and cardiac-specific knockouts), in myocytes subjected to acute hyperglycemia and Ang II (angiotensin II) and mice after streptozotocin injections (to induce diabetes). Human patients with diabetes exhibit elevated CaMKII O-GlcNAcylation but not oxidation. In mice, acute hyperglycemia increased spontaneous diastolic Ca(2+) sparks and waves and arrhythmogenic action potential changes (prolongation, alternans, and delayed afterdepolarizations), all of which required CaMKII-S280 O-GlcNAcylation. Ang II effects were dependent on NOX2 (NADPH oxidase 2)-mediated CaMKII MM281/2 oxidation. Diabetes led to much greater Ca(2+) leak, RyR2 S2814 phosphorylation, electrophysiological remodeling, and increased susceptibility to in vivo arrhythmias, requiring CaMKII activation, predominantly via S280 O-GlcNAcylation and less via MM281/2 oxidation. These effects were present in myocytes at normal glucose but were exacerbated with the in vivo high circulating glucose. PLB (phospholamban) O-GlcNAcylation was increased and coincided with reduced PLB S16 phosphorylation in diabetes. Dantrolene, which reverses CaMKII-dependent proarrhythmic RyR-mediated Ca(2+) leak, also prevented hyperglycemia-induced APD prolongation and delayed afterdepolarizations. CONCLUSIONS: We found that CaMKII-S280 O-GlcNAcylation is required for increased arrhythmia susceptibility in diabetic hyperglycemia, which can be worsened by an additional Ang II-NOX2-CaMKII MM281/2 oxidation pathway. CaMKII-dependent RyR2 S2814 phosphorylation markedly increases proarrhythmic Ca(2+) leak and PLB O-GlcNAcylation may limit sarcoplasmic reticulum Ca(2+) reuptake, leading to impaired excitation-contraction coupling and arrhythmogenesis in diabetic hyperglycemia.
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spelling pubmed-82215392021-06-23 CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia Hegyi, Bence Fasoli, Anna Ko, Christopher Y. Van, Benjamin W. Alim, Chidera C. Shen, Erin Y. Ciccozzi, Marisa M. Tapa, Srinivas Ripplinger, Crystal M. Erickson, Jeffrey R. Bossuyt, Julie Bers, Donald M. Circ Res Original Research RATIONALE: Diabetic hyperglycemia is associated with cardiac dysfunction and increased arrhythmia risk, and CaMKII (calcium/calmodulin-dependent protein kinase II) function has been implicated. CaMKII activity is promoted by both oxidation and O-linked β-N-acetylglucosamine (O-GlcNAc) of known CaMKII sites. OBJECTIVE: To investigate which posttranslational modifications occur in human diabetic hearts and how they alter electrophysiological and Ca(2+) handling properties in hyperglycemia. METHODS AND RESULTS: We assessed echocardiography, electrophysiology, Ca(2+)-handling, and protein expression in site-specific CaMKII mutant mice (O-GlcNAc-resistant S280A and oxidation-resistant MM281/2VV knock-ins, and global and cardiac-specific knockouts), in myocytes subjected to acute hyperglycemia and Ang II (angiotensin II) and mice after streptozotocin injections (to induce diabetes). Human patients with diabetes exhibit elevated CaMKII O-GlcNAcylation but not oxidation. In mice, acute hyperglycemia increased spontaneous diastolic Ca(2+) sparks and waves and arrhythmogenic action potential changes (prolongation, alternans, and delayed afterdepolarizations), all of which required CaMKII-S280 O-GlcNAcylation. Ang II effects were dependent on NOX2 (NADPH oxidase 2)-mediated CaMKII MM281/2 oxidation. Diabetes led to much greater Ca(2+) leak, RyR2 S2814 phosphorylation, electrophysiological remodeling, and increased susceptibility to in vivo arrhythmias, requiring CaMKII activation, predominantly via S280 O-GlcNAcylation and less via MM281/2 oxidation. These effects were present in myocytes at normal glucose but were exacerbated with the in vivo high circulating glucose. PLB (phospholamban) O-GlcNAcylation was increased and coincided with reduced PLB S16 phosphorylation in diabetes. Dantrolene, which reverses CaMKII-dependent proarrhythmic RyR-mediated Ca(2+) leak, also prevented hyperglycemia-induced APD prolongation and delayed afterdepolarizations. CONCLUSIONS: We found that CaMKII-S280 O-GlcNAcylation is required for increased arrhythmia susceptibility in diabetic hyperglycemia, which can be worsened by an additional Ang II-NOX2-CaMKII MM281/2 oxidation pathway. CaMKII-dependent RyR2 S2814 phosphorylation markedly increases proarrhythmic Ca(2+) leak and PLB O-GlcNAcylation may limit sarcoplasmic reticulum Ca(2+) reuptake, leading to impaired excitation-contraction coupling and arrhythmogenesis in diabetic hyperglycemia. Lippincott Williams & Wilkins 2021-04-30 2021-06-25 /pmc/articles/PMC8221539/ /pubmed/33926209 http://dx.doi.org/10.1161/CIRCRESAHA.120.318402 Text en © 2021 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.
spellingShingle Original Research
Hegyi, Bence
Fasoli, Anna
Ko, Christopher Y.
Van, Benjamin W.
Alim, Chidera C.
Shen, Erin Y.
Ciccozzi, Marisa M.
Tapa, Srinivas
Ripplinger, Crystal M.
Erickson, Jeffrey R.
Bossuyt, Julie
Bers, Donald M.
CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia
title CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia
title_full CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia
title_fullStr CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia
title_full_unstemmed CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia
title_short CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia
title_sort camkii serine 280 o-glcnacylation links diabetic hyperglycemia to proarrhythmia
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221539/
https://www.ncbi.nlm.nih.gov/pubmed/33926209
http://dx.doi.org/10.1161/CIRCRESAHA.120.318402
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