Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via O-linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes.

Circulation Research
Shan LuDonald M Bers

Abstract

Diabetes mellitus is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII (Ca2+/calmodulin-dependent kinase II) activation may occur in diabetes mellitus and be arrhythmogenic. Diabetic hyperglycemia was shown to activate CaMKII by (1) O-linked attachment of N-acetylglucosamine (O-GlcNAc) at S280 leading to arrhythmia and (2) a reactive oxygen species (ROS)-mediated oxidation of CaMKII that can increase postinfarction mortality. To test whether high extracellular glucose (Hi-Glu) promotes ventricular myocyte ROS generation and the role played by CaMKII. We tested how extracellular Hi-Glu influences ROS production in adult ventricular myocytes, using DCF (2',7'-dichlorodihydrofluorescein diacetate) and genetically targeted Grx-roGFP2 redox sensors. Hi-Glu (30 mmol/L) significantly increased the rate of ROS generation-an effect prevented in myocytes pretreated with CaMKII inhibitor KN-93 or from either global or cardiac-specific CaMKIIδ KO (knockout) mice. CaMKII KO or inhibition also prevented Hi-Glu-induced sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks). Thus, CaMKII activation is required for Hi-Glu-induced ROS generation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes. To test...Continue Reading

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Citations

May 8, 2020·Circulation Research·Johannes Backs
Jan 3, 2021·Journal of Molecular and Cellular Cardiology·Qinfeng LiZhao V Wang
Nov 26, 2020·Basic Research in Cardiology·Bence HegyiDonald M Bers
Nov 6, 2020·The Journal of Clinical Investigation·Olurotimi O MesubiMark E Anderson
Jan 24, 2021·Free Radical Biology & Medicine·Maija DambrovaMarina Makrecka-Kuka
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Mar 22, 2021·Cardiovascular Research·Raffaele Coppini, Elisabetta Cerbai
May 22, 2021·Free Radical Biology & Medicine·David Weissman, Christoph Maack
Jun 9, 2021·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Pradnya ShahaniIndrani Datta
Jun 1, 2021·Acta Physiologica·Yann Huey NgPeter P Jones
May 1, 2021·Circulation Research·Bence HegyiDonald M Bers
Jul 25, 2021·International Journal of Molecular Sciences·Natthaphat Siri-AngkulJudith K Gwathmey
Aug 13, 2021·Frontiers in Pharmacology·Christopher R VeitchJeffrey R Erickson
Aug 10, 2021·Journal of Molecular and Cellular Cardiology·Mitchell SimonDonald M Bers
Nov 16, 2020·Archives of Cardiovascular Diseases·Sylvain BattaultLuc Bertrand

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Methods Mentioned

BETA
confocal microscopy
immunoprecipitation
FRET
transgenic

Software Mentioned

GraphPad

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