Arecoline induces cardiotoxicity by upregulating and activating cardiac hypertrophy-related pathways in Sprague–Dawley rats

Habitual chewing of the areca nut increases the risk of mortality owing to cardiovascular disease, but few reports have revealed the cardiotoxicity mechanism of the areca nut. Arecoline has been reported to be the primary toxic constituent in the areca nut. In order to study the acute cardiotoxicity...

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Published in:Chemico-biological interactions 2022-02, Vol.354, p.109810, Article 109810
Main Authors: Ho, Tsung-Jung, Chi-Kang Tsai, Bruce, Kuo, Chia-Hua, Luk, Hsiang-Ning, Day, Cecilia Hsuan, Jine-Yuan Hsieh, Dennis, Chen, Ray-Jade, Kuo, Wei-Wen, Kumar, V. Bharath, Yao, Chun-Hsu, Huang, Chih-Yang
Format: Article
Language:English
Subjects:
Areca nut
Arecoline
Calcineurin
Cardiac toxicity
IL-6
MAPK
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Summary:Habitual chewing of the areca nut increases the risk of mortality owing to cardiovascular disease, but few reports have revealed the cardiotoxicity mechanism of the areca nut. Arecoline has been reported to be the primary toxic constituent in the areca nut. In order to study the acute cardiotoxicity of the areca nut in the development of pathologic heart hypertrophy, we induced heart injury in rats using arecoline. Arecoline at a low dosage (5 mg/kg/day) or a high dosage (50 mg/kg/day) was intraperitoneally injected to Sprague–Dawley rats for 21 days. The change of heart function and biochemical pathways were investigated with echocardiography and Western blot. The results were presented that heart functions were weakened by arecoline stimulation, and western blotting analysis revealed an elevation in BNP levels in the heart after arecoline exposure. Arecoline induced IL-6-mediated activation of the MEK5/ERK5 and JAK2/STAT3 pathways, as well as mitogen-activated protein kinase signaling cascades. Further, arecoline increased the calcineurin and NFATc3 levels in the heart. In summary, our results suggest that arecoline causes significantly cardiotoxicity and heart damage by inducing several hypertrophy-related signaling pathways, including IL-6-induced MEK5/ERK5, JAK2/STAT3, mitogen-activated protein kinases, and calcineurin signaling pathways. The study elucidated, for the first time, the possible cardiac hypertrophy mechanisms underlying the cardiotoxicity of the areca nut. •Chewing of areca nut increases the mortality owing to cardiovascular disease.•Arecoline leads to hypertrophic cardiomyopathy in rat model.•IL-6-mediated MEK5-ERK5 and JAK2-STAT3 pathways are induced with arecoline.•MAPK and calcineurin/NFATc3 hypertrophy pathways are activated with arecoline.•The study elucidates the relevant knowledge about cardiotoxicity of areca nut.
ISSN:0009-2797
1872-7786
1872-7786
DOI:10.1016/j.cbi.2022.109810