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

Tsung-Jung Ho; Bruce Chi-Kang Tsai; Chia-Hua Kuo; Hsiang-Ning Luk; Cecilia Hsuan Day; Dennis Jine-Yuan Hsieh; Ray-Jade Chen; Wei-Wen Kuo; V Bharath Kumar; Chun-Hsu Yao; Chih-Yang Huang

doi:10.1016/j.cbi.2022.109810

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

Chem Biol Interact. 2022 Feb 25:354:109810. doi: 10.1016/j.cbi.2022.109810. Epub 2022 Jan 7.

Authors

Affiliations

¹ Integration Center of Traditional Chinese and Modern Medicine, HualienTzu Chi Hospital, Hualien, Taiwan; Department of Chinese Medicine,Hualien Tzu Chi Hospital, Hualien, Taiwan; School of Post-Baccalaure-ate Chinese Medicine, College of Medicine, Tzu Chi University, Hualien, Taiwan.
² Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
³ Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan; Department of Kinesiology and Health Science, College of William and Mary, Williamsburg, VA, USA.
⁴ Department of Anesthesia, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.
⁵ Department of Nursing, MeiHo University, Pingtung, Taiwan.
⁶ Department of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan.
⁷ Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
⁸ Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung, Taiwan; Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, Taiwan.
⁹ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
¹⁰ Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, Taiwan; Biomaterials Translational Research Center, China Medical University Hospital, Taichung, Taiwan; Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
¹¹ Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: cyhuang@mail.cmu.edu.tw.

PMID: 34999050
DOI: 10.1016/j.cbi.2022.109810

Abstract

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.

Keywords: Areca nut; Arecoline; Calcineurin; Cardiac toxicity; IL-6; MAPK.

MeSH terms

Arecoline*

Substances

Arecoline