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

被引：13

作者：

Prathumsap, Nanthip ^{[1
,2
,3
]}

Ongnok, Benjamin ^{[1
,2
,3
]}

Khuanjing, Thawatchai ^{[1
,2
,3
]}

Arinno, Apiwan ^{[1
,2
,3
]}

Maneechote, Chayodom ^{[1
,3
]}

Apaijai, Nattayaporn ^{[1
,2
,3
]}

Chunchai, Titikorn ^{[1
,3
]}

Arunsak, Busarin ^{[1
,3
]}

Kerdphoo, Sasiwan ^{[1
,3
]}

Janjek, Sornram ^{[1
,3
]}

Chattipakorn, Siriporn C. ^{[1
,3
,4
]}

Chattipakorn, Nipon ^{[1
,2
,3
]}

机构：

[1] Chiang Mai Univ, Fac Med, Cardiac Electrophysiol Res & Training Ctr, Chiang Mai 50200, Thailand

[2] Chiang Mai Univ, Fac Med, Dept Physiol, Cardiac Electrophysiol Unit, Chiang Mai 50200, Thailand

[3] Chiang Mai Univ, Ctr Excellence Cardiac Electrophysiol, Chiang Mai 50200, Thailand

[4] Chiang Mai Univ, Fac Dent, Dept Oral Biol & Diagnost Sci, Chiang Mai 50200, Thailand

来源：

CELLULAR AND MOLECULAR LIFE SCIENCES | 2023年 / 80卷 / 01期

关键词：

Vagus nerve stimulation; Doxorubicin; Cardiotoxicity; Programmed cell death; HEART-FAILURE; MITOCHONDRIAL DYNAMICS; H9C2; CELLS; APOPTOSIS; MECHANISMS; AUTOPHAGY; IMPROVES; THYMOQUINONE; PATHOGENESIS; NECROPTOSIS;

D O I：

10.1007/s00018-022-04678-4

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：22

共 90 条

[21] Vagus Nerve Stimulation for the Treatment of Heart Failure The INOVATE-HF Trial [J].