Abstract
The areca nut is one of the most commonly consumed psychoactive substances worldwide, with an estimated consumption by approximately 10% of the world’s population, especially in some regions of South Asia, East Africa, and the tropical Pacific. Arecoline, the major areca nut alkaloid, has been classified as carcinogenic to humans as it adversely affects various organs, including the brain, heart, lungs, gastrointestinal tract, and reproductive organs. Earlier studies have established a link between areca nut chewing and cardiac arrhythmias, and yet research pertaining to the mechanisms underlying cardiotoxicity caused by arecoline is still preliminary. The main purpose of this study is to test the hypothesis that arecoline causes cardiac fibrosis through transforming growth factor-β (TGF-β)/Smad-mediated signaling pathways. Male Wistar rats were injected intraperitoneally with low (5 mg/kg/day) or high (50 mg/kg/day) doses of arecoline for 3 weeks. Results from Masson’s trichrome staining indicated that arecoline could induce cardiac fibrosis through collagen accumulation. Western blot analysis showed that TGF-β and p-Smad2/3 protein expression levels were markedly higher in the arecoline-injected rat hearts than in those of the control rats. Moreover, arecoline upregulated other fibrotic-related proteins, including SP1-mediated connective tissue growth factor expression. Tissue-type plasminogen activator and its inhibitor, plasminogen activator inhibitor, and matrix metalloproteinase (MMP) 9 were upregulated, and the inhibitor of MMP9 was downregulated. This study provides novel insight into the molecular mechanisms underlying arecoline-induced cardiac fibrosis. Taken together, the areca nut is a harmful substance, and the detrimental effects of arecoline on the heart are similar to that caused by oral submucous fibrosis.
Highlights
Arecoline-induced collagen deposition through multisignaling pathways has been postulated as the primary causative event for increased collagen production in oral submucous fibrosis [7]
To investigate the pro-fibrotic protein expression signaling pathways affected by arecoline, we first assessed the levels of molecules involved in the progress of cardiac remodeling, namely TGF-β1 and p-Smad2/3, in control, low-dose arecoline, and high-dose arecoline rats
The TGF-β1 expression was slightly lower in the low-dose arecoline rats compared to the control rats, and it exhibited an approximately 1.7-fold increase in high-dose arecoline rats compared to the control rats (Figure 4)
Summary
More than 600 million people are regular consumers of areca nuts, especially people in Asian populations [1]. Ethanol, and caffeine, the areca nut is considered the fourth most commonly abused substances by people [2]. Numerous psychiatric studies have shown that chronic areca nut chewers are prone to developing drug dependence, and their presenting symptoms meet the criteria for a substance use disorder of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [3]. Chewing the areca nut usually slightly elevates the body temperature and causes people to feel energetic, euphoric, and vigilant. Several epidemiological studies have demonstrated that chronic areca nut chewers can develop systematic diseases in various organs, including the brain, heart, lungs, gastrointestinal tract, reproductive organs, and immune system [4]. Consuming areca nuts has been demonstrated to cause hyperlipidemia, vasospasm, and cardiac arrhythmias, which can subsequently lead to an increased risk of myocardial ischemia [5]. Information regarding the cardiac dysfunction caused by arecoline is relatively limited
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