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Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy
Eric Himelman, … , Jorge E. Contreras, Diego Fraidenraich
Eric Himelman, … , Jorge E. Contreras, Diego Fraidenraich
Published January 7, 2020
Citation Information: J Clin Invest. 2020;130(4):1713-1727. https://doi.org/10.1172/JCI128190.
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Research Article Cardiology Cell biology Article has an altmetric score of 49

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy

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Abstract

Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking. Here, we identified a reduction of phosphorylation of Cx43 serines S325/S328/S330 in human and mouse DMD hearts. We hypothesized that hypophosphorylation of Cx43 serine-triplet triggers pathological Cx43 redistribution to the lateral sides of cardiomyocytes (remodeling). Therefore, we generated knockin mdx mice in which the Cx43 serine-triplet was replaced with either phospho-mimicking glutamic acids (mdxS3E) or nonphosphorylatable alanines (mdxS3A). The mdxS3E, but not mdxS3A, mice were resistant to Cx43 remodeling, with a corresponding reduction of Cx43 hemichannel activity. MdxS3E cardiomyocytes displayed improved intracellular Ca2+ signaling and a reduction of NADPH oxidase 2 (NOX2)/ROS production. Furthermore, mdxS3E mice were protected against inducible arrhythmias, related lethality, and the development of cardiomyopathy. Inhibition of microtubule polymerization by colchicine reduced both NOX2/ROS and oxidized CaMKII, increased S325/S328/S330 phosphorylation, and prevented Cx43 remodeling in mdx hearts. Together, these results demonstrate a mechanism of dystrophic Cx43 remodeling and suggest that targeting Cx43 may be a therapeutic strategy for preventing heart dysfunction and arrhythmias in DMD patients.

Authors

Eric Himelman, Mauricio A. Lillo, Julie Nouet, J. Patrick Gonzalez, Qingshi Zhao, Lai-Hua Xie, Hong Li, Tong Liu, Xander H.T. Wehrens, Paul D. Lampe, Glenn I. Fishman, Natalia Shirokova, Jorge E. Contreras, Diego Fraidenraich

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Figure 2

Cx43 remodeling is prevented in mdxS3E hearts.

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Cx43 remodeling is prevented in mdxS3E hearts.
(A) Representative immuno...
(A) Representative immunofluorescence images of mouse heart cryosections stained for pan-Cx43 (green) and visualized for WGA (lipid bilayer marker, red) or N-cadherin (ID marker, red). Scale bar: 25 μm. (B) Representative confocal immunofluorescence images of cardiac IDs and lateral regions of cardiomyocytes stained with pan-Cx43 (green) and N-cadherin (red). White arrows indicate costaining of Cx43 and N-cadherin; red arrows indicate lateralized Cx43. Scale bars: 5 μm. (C) Quantification of Cx43/N-cadherin colocalization in confocal immunofluorescence images. All data points were normalized to the WT group mean. n = 8 (WT); n = 10 (mdx); n = 9 (mdxS3A); n = 9 (mdxS3E). Three to five images containing 15-20 IDs were analyzed per heart. Each dot represents a mean value per mouse. (D) Representative Western blots (top) and quantification (bottom) of Cx43 from biotin-perfused hearts. Top Western blot row represents biotinylated Cx43 protein signals, middle row represents total Cx43, and bottom row represents Ponceau S staining for loading. Ponceau S stain was used for loading, since we cannot detect cytosolic loading controls through biotinylation. Quantification (bottom) of biotinylated Cx43 levels was expressed as fold change relative to total Cx43 protein levels per sample. Data were normalized to WT mean group value (n = 4 per group). Data are presented as mean ± SEM. ****P < 0.0001; *P < 0.05 versus WT; #P < 0.05 versus mdx. Statistical significance determined by 1-way ANOVA followed by Tukey’s post hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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