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Citations to this article

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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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 Total
Citations: 3 6 6 16 13 4 48
Citation information
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Citations to this article (48)

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Overexpression of Cx43: Is It an Effective Approach for the Treatment of Cardiovascular Diseases?
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Downregulation of EB1 impedes Cx43 localization and cardiac conduction after hypothermic ischemia-reperfusion in rats
Wen C, Yang R, Yi J, Cao Y, Song Y, An L, Wang Z, Gao H
PeerJ 2025
Casein Kinase 1 Phosphomimetic Mutations Negatively Impact Connexin-43 Gap Junctions in Human Pluripotent Stem Cell-Derived Cardiomyocytes.
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Biomolecules 2024
KLF5 promotes the ossification process of ligamentum flavum by transcriptionally activating CX43.
Guo H, Yang L, Liu J, Chen L, Huang Y, Li J
Journal of orthopaedic surgery and research 2024
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International journal of molecular sciences 2024
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Burboa PC, Gaete PS, Shu P, Araujo PA, Beuve AV, Durán WN, Contreras JE, Lillo MA
bioRxiv : the preprint server for biology 2024
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Barreto BC, Neves MV, Cardoso CM, Meira CS, Daltro PS, Figueira CP, Santos GC, Silva DN, Távora F, Neto JD, Macambira SG, Lampe PD, Coutinho KC, Kasai Brunswick TH, Ribeiro dos Santos R, Campos de Carvalho AC, Soares MB
Frontiers in Immunology 2024
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Role of Connexin 43 phosphorylation on Serine-368 by PKC in cardiac function and disease
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Physiological reviews 2023
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Lillo MA, Muñoz M, Rhana P, Gaul-Muller K, Quan J, Shirokova N, Xie LH, Santana LF, Fraidenraich D, Contreras JE
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Connexin 43 Phosphorylation: Implications in Multiple Diseases
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Microtubule-Connexin-43 bi-directional regulation suppresses arrhythmias and fibrosis in Duchenne muscular dystrophy mice.
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