期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 4, 页码 1713-1727出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI128190
关键词
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资金
- American Heart Association (AHA) predoctoral fellowship [17PRE33660354]
- AHA postdoctoral fellowship [18POST339610107]
- NIH [NS046593, 1R01HL141170-01, R01GM099490, HL093342, R01HL92929, R01Hl133294, R01HL82727, GM55632, R01GM112415, P30NS046593]
- AHA [16GRNT31100022]
- Muscular Dystrophy Association [602349, 416281]
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.
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