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Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways

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Abstract

The aberration of programmed cell death including cell death associated with autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis can be observed in the development and progression of doxorubicin-induced cardiotoxicity (DIC). Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against cardiomyocyte death through the release of the neurotransmitter acetylcholine (ACh) under a variety of pathological conditions. However, the roles of VNS and its underlying mechanisms against DIC have never been investigated. Forty adults male Wistar rats were divided into 5 experimental groups: (i) control without VNS (CSham) group, (ii) doxorubicin (3 mg/kg/day, i.p.) without VNS (DSham) group, (iii) doxorubicin + VNS (DVNS) group, (iv) doxorubicin + VNS + mAChR antagonist (atropine; 1 mg/kg/day, ip, DVNS + Atro) group, and (v) doxorubicin + VNS + nAChR antagonist (mecamylamine; 7.5 mg/kg/day, ip, DVNS + Mec) group. Our results showed that doxorubicin insult led to left ventricular (LV) dysfunction through impaired cardiac autonomic balance, decreased mitochondrial function, imbalanced mitochondrial dynamics, and exacerbated cardiomyocyte death including autophagy/mitophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. However, VNS treatment improved cardiac mitochondrial and autonomic functions, and suppressed excessive autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis, leading to improved LV function. Consistent with this, ACh effectively improved cell viability and suppressed cell cytotoxicity in doxorubicin-treated H9c2 cells. In contrast, either inhibitors of muscarinic (mAChR) or nicotinic acetylcholine receptor (nAChR) completely abrogated the favorable effects mediated by VNS and acetylcholine. These findings suggest that VNS exerts cardioprotective effects against doxorubicin-induced cardiomyocyte death via activation of both mAChR and nAChR.

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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.

Code availability

Not applicable.

Abbreviations

Atro:

Atropine

CSham:

Control + sham

CO:

Cardiac output

DBP:

Diastolic blood pressure

DSham:

Doxorubicin + sham

DVNS:

Doxorubicin + VNS

DIC:

Doxorubicin-induced cardiotoxicity

DOX:

Doxorubicin

Drp1:

Dynamin-related protein 1

E/A:

Early filling to atrial filling velocities ratio

EF:

Ejection fraction

FS:

Fractional shortening

EDP:

End-diastolic pressure

ESP:

End-systolic pressure

HRV:

Heart rate variability

IL-6:

Interleukin-6

LDH:

Lactate dehydrogenase

LF/HF:

Low frequency/high frequency

Mec:

Mecamylamine

mAChR:

Muscarinic acetylcholine receptors

MDA:

Malondialdehyde

Mfn1-2:

Mitofusin1-2

nAChR:

Nicotinic acetylcholine receptor

P–V loop:

Pressure–volume loop

RT-PCR:

Real-time polymerase chain reaction

ROS:

Reactive oxygen species

SV:

Stroke volume

SBP:

Systolic blood pressure

TEM:

Transmission electron microscopy

TNF-α:

Tumor necrosis factor-alpha

VNS:

Vagus nerve stimulation

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Funding

This work was supported by a NSTDA Research Chair grant from the National Science and Technology Development Agency Thailand (NC), the Senior Research Scholar grant from the National Research Council of Thailand (SCC), Thailand Research Fund-Royal Golden Jubilee Program PHD/0105/2561 (NP and NC), and the Chiang Mai University Center of Excellence Award (NC).

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Authors and Affiliations

  1. Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Nanthip Prathumsap, Benjamin Ongnok, Thawatchai Khuanjing, Apiwan Arinno, Chayodom Maneechote, Nattayaporn Apaijai, Titikorn Chunchai, Busarin Arunsak, Sasiwan Kerdphoo, Sornram Janjek, Siriporn C. Chattipakorn & Nipon Chattipakorn

  2. Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand

    Nanthip Prathumsap, Benjamin Ongnok, Thawatchai Khuanjing, Apiwan Arinno, Nattayaporn Apaijai & Nipon Chattipakorn

  3. Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand

    Nanthip Prathumsap, Benjamin Ongnok, Thawatchai Khuanjing, Apiwan Arinno, Chayodom Maneechote, Nattayaporn Apaijai, Titikorn Chunchai, Busarin Arunsak, Sasiwan Kerdphoo, Sornram Janjek, Siriporn C. Chattipakorn & Nipon Chattipakorn

  4. Department of Oral Biology and Diagnostic Science, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand

    Siriporn C. Chattipakorn

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  1. Nanthip Prathumsap
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  2. Benjamin Ongnok
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  12. Nipon Chattipakorn
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Contributions

SCC and NC designed the experiments. NP, BO, TK, AA, CM, NA, TC, BA, SK, SJ conducted the experiments. NP, SCC, and NC analyzed the data, wrote the manuscript, and finalized the manuscript. All authors reviewed and provided critical comments on the manuscript. NP and NC are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Nipon Chattipakorn.

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Prathumsap, N., Ongnok, B., Khuanjing, T. et al. Vagus nerve stimulation exerts cardioprotection against doxorubicin-induced cardiotoxicity through inhibition of programmed cell death pathways. Cell. Mol. Life Sci. 80, 21 (2023). https://doi.org/10.1007/s00018-022-04678-4

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