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S-nitrosylation of connexin43 hemichannels elicits cardiac stress–induced arrhythmias in Duchenne muscular dystrophy mice
Mauricio A. Lillo, … , Diego Fraidenraich, Jorge E. Contreras
Mauricio A. Lillo, … , Diego Fraidenraich, Jorge E. Contreras
Published November 12, 2019
Citation Information: JCI Insight. 2019;4(24):e130091. https://doi.org/10.1172/jci.insight.130091.
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Research Article Muscle biology

S-nitrosylation of connexin43 hemichannels elicits cardiac stress–induced arrhythmias in Duchenne muscular dystrophy mice

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Abstract

Patients with Duchenne muscular dystrophy (DMD) commonly present with severe ventricular arrhythmias that contribute to heart failure. Arrhythmias and lethality are also consistently observed in adult Dmdmdx mice, a mouse model of DMD, after acute β-adrenergic stimulation. These pathological features were previously linked to aberrant expression and remodeling of the cardiac gap junction protein connexin43 (Cx43). Here, we report that remodeled Cx43 protein forms Cx43 hemichannels in the lateral membrane of Dmdmdx cardiomyocytes and that the β-adrenergic agonist isoproterenol (Iso) aberrantly activates these hemichannels. Block of Cx43 hemichannels or a reduction in Cx43 levels (using Dmdmdx Cx43+/– mice) prevents the abnormal increase in membrane permeability, plasma membrane depolarization, and Iso-evoked electrical activity in these cells. Additionally, Iso treatment promotes nitric oxide (NO) production and S-nitrosylation of Cx43 hemichannels in Dmdmdx heart. Importantly, inhibition of NO production prevents arrhythmias evoked by Iso. We found that NO directly activates Cx43 hemichannels by S-nitrosylation of cysteine at position 271. Our results demonstrate that opening of remodeled and S-nitrosylated Cx43 hemichannels plays a key role in the development of arrhythmias in DMD mice and that these channels may serve as therapeutic targets to prevent fatal arrhythmias in patients with DMD .

Authors

Mauricio A. Lillo, Eric Himelman, Natalia Shirokova, Lai-Hua Xie, Diego Fraidenraich, Jorge E. Contreras

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Figure 1

Isoproterenol induces triggered activity in Dmdmdx cardiomyocytes via opening of Cx43 hemichannels.

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Isoproterenol induces triggered activity in Dmdmdx cardiomyocytes via op...
(A) Representative action potential (AP) traces of WT, Dmdmdx, and Dmdmdx Cx43+/– isolated cardiomyocytes. Cells were stimulated with 1 μM isoproterenol (Iso, shown in green) in the absence or presence of Cx43 or Cx45 hemichannel blockers contained inside the pipette: Gap19 (232 ng/μL), Cx43 CT antibody (abCx43; 2.5 ng/μL), or Cx45 CT antibody (2.5 ng/μL). Arrow indicates electrical stimulation pulse. (B) Quantification of triggered activity (TA) induced by Iso observed in A. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05. (C) Resting membrane potential of WT and Dmdmdx cardiomyocytes. The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test; *P < 0.05. (D) Assessment of Cx43 hemichannel activity in the whole heart via ethidium uptake. Isolated hearts were perfused with buffer containing 5 μM ethidium after vehicle or Iso (5 mg/kg IP). The number in parentheses indicates the n value. Comparisons between groups were made using 2-way ANOVA plus Tukey’s post hoc test. *P < 0.05 vs. vehicle WT; †P < 0.05 vs. vehicle Dmdmdx.

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