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. 2021 Sep 8;11:17808. doi: 10.1038/s41598-021-97449-3

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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CaMK inhibitor cardiomyocytes are protected from ROS and mitochondrial dysfunction, and CaMK inhibitor hearts are protected from ventricular tachycardia and repolarization dispersion after HFD. (A) Isolated WT and CaMKi transgenic cardiomyocytes, ± palmitate, height is DCF fluorescence minus background, mean + SEM, n = triplicate wells, 2000 cells per well. (B) WT and CaMKi transgenic cardiomyocytes, mitosox red signal. (C) WT and CaMKi transgenic cardiomyocytes, Rhod2AM signal for mitochondrial calcium. (D) WT and CaMKi transgenic cardiomyocytes, TMRM signal to indicate mitochondrial inner membrane potential. For (A–D), similar results were obtained from 3 different isolations for each genotype. (E) Example of a longer episode of burst-pacing induced VT from a WT HFD heart, followed by several beats of junction rhythm (JR, note the absence of p-waves) and then sinus rhythm resumes. Time scale: each vertical thick line is 500 ms, each thin line is 100 ms. (F) Graph of number of episodes of VT from control and CaMKi hearts induced by rapid ventricular pacing. N = 4–6 hearts per group. The differences between groups are statistically significant by nonparametric Kruskal–Wallis test, p = 0.014. (G) Graph of action potential duration 50% (APD50). The means are significantly different by ANOVA, *Indicates significantly different from control by post-hoc test. (H) Graph of action potential duration 80% (APD80). The means are significantly different by ANOVA, *Indicates significantly different from control by post-hoc test. (I) Graph of APD dispersion, n = 4–6 hearts per group, the means are significantly different by ANOVA, *Indicates significantly different by post-hoc test. (J) Schematic of proposed mechanism. Saturated fatty acid increases oxidative stress in cardiomyocytes by activating NOX. This causes increase calcium leak from the sarcoplasmic reticulum, leading to mitochondrial calcium overload and mitochondrial dysfunction. Preventing mitochondrial calcium overload is protective. This pathophysiology is exacerbated by CaMK activation. MCU mitochondrial calcium uniporter, NOX2 NADPH oxidase 2, ROS reactive oxygen species, RyR2 ryanodine receptor 2, SR sarcoplasmic reticulum.