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The activation of P38MAPK Signaling Pathway Impedes the Delivery of the Cx43 to the Intercalated Discs During Cardiac Ischemia–Reperfusion Injury

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Abstract

Ischemic heart disease is caused by coronary artery occlusion. Despite the increasing number and success of interventions for restoring coronary artery perfusion, myocardial ischemia–reperfusion (I/R) injury remains a significant cause of morbidity and mortality worldwide. Inspired by the impact of I/R on the Cx43 trafficking to the intercalated discs (ICDs), we aim to explore the potential mechanisms underlying the downregulation of Cx43 in ICDs after myocardial I/R. Gene set enrichment analysis (GSEA), Western blotting, and immunofluorescence experiments showed that Myocardial I/R activated the P38MAPK signaling pathway and promoted microtubule depolymerization. Inhibition of P38MAPK signaling pathway activation attenuated I/R-induced microtubule depolymerization. The ability of SB203580 to recover the distribution of Cx43 and electrophysiological parameters in I/R myocardium depended on microtubule stability. Our study suggests that microtubule depolymerization caused by the activation of the P38MAPK signaling pathway is an important mechanism underlying the downregulation of Cx43 in ICDs after myocardial I/R.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

DMEM:

Dulbecco’s modified Eagle’s medium; DMSO: Dimethyl sulfoxide;

ECG:

Electrocardiography; GOBP: Gene Ontology Biological Process;

GSEA:

Gene set enrichment analysis; ICDs: intercalated discs;

IHD:

Ischemic heart disease; I/R: Ischemia–reperfusion;

MAPs:

Microtubule-associated proteins;

MIRI:

Myocardial ischemic-reperfusion injury; SPF: Specific pathogen-free

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Acknowledgements

We thank Figdraw (www.figdraw.com) for their help in creating the schematic representation of the experimental protocol.

Funding

This study was supported by grants from the Science and Technology Fund Project of the Guizhou Provincial Health Commission (gzwkj2021-270, Gzwkj2022-131).

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Author notes

  1. Xiang Huang and Xue Bai contributed equally to this study.

Authors and Affiliations

  1. Department of Anesthesiology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou, China

    Xiang Huang, Xue Bai, Jing Yi, Tingju Hu & Li An

  2. Guizhou Hospital, Branch of the First Affiliated Hospital of Sun Yat-Sen University, Guiyang, 550004, Guizhou, China

    Hong Gao

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  1. Xiang Huang
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Correspondence to Hong Gao.

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No human studies were carried out by the authors for this article. The protocol of the experiments was approved by the Ethics Committee of Guizhou Medical University (approval number: 2303066). The animal care and use protocol was adhered to the Chinese National Laboratory Animal-Guideline for Ethical Review of Animal Welfare (GB/T 35892–2018).

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Huang, X., Bai, X., Yi, J. et al. The activation of P38MAPK Signaling Pathway Impedes the Delivery of the Cx43 to the Intercalated Discs During Cardiac Ischemia–Reperfusion Injury. J. of Cardiovasc. Trans. Res. (2024). https://doi.org/10.1007/s12265-024-10515-9

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