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. 2021 Apr 30;129(1):98–113. doi: 10.1161/CIRCRESAHA.120.318402

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© 2021 The Authors.

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 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.

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Figure 2. — Glucose-induced diastolic sarcoplasmic reticulum (SR) Ca²⁺ leak is CaMKIIδ (Ca²⁺/calmodulin-dependent protein kinase II)-S280 O-GlcNAcylation dependent. A, Experimental protocol and representative intracellular Ca²⁺ signals (quantified as changes in Fluo-4 fluorescence). B, High-glucose treatment (540 mg/dL, 6 min) did not change the amplitude and decay of intracellular Ca²⁺ transient (CaT) but reduced SR Ca²⁺ load similarly in CaMKIIδ wild type (WT), cardiac-specific knockout (cKO), and O-GlcNAc-resistant CaMKIIδ-S280A knock-in (n[CaT]=total number of cells/animals, WT/normal glucose=24/8, WT/high-glucose=13/8, cKO/normal glucose=15/7, cKO/high-glucose=10/7, S280A/normal glucose=17/6, S280A/high-glucose=11/6; n[SR load]= total number of cells/animals, WT=20/11, cKO=13/9, S280A=18/9). Nested t test. C, Representative diastolic Ca²⁺ sparks were increased by high-glucose treatment in WT which was prevented in cKO and S280A. D, Increased Ca²⁺ spark frequency normalized to SR load indicates sensitized, leaky ryanodine receptors (n=total number of cells/animals, WT=20/11, cKO=13/9, S280A=18/9). Nested t test. E, Enhanced fluorescence recovery after photobleaching (FRAP) by high-glucose treatment in cardiomyocytes expressing GFP (green fluorescent protein)-tagged WT-CaMKIIδ (n=16 cells from 6 animals in normal glucose and n=13 cells from 6 animals in high-glucose) but not in GFP-CaMKIIδ-S280A (n=16 cells from 6 animals in both normal and high-glucose) indicates increased activation-dependent mobility of CaMKIIδ. Nested t test.