Abstract
Direct exposure of cardiomyocytes to ethanol causes cardiac damage such as cardiac arrythmias and apoptotic cell death. Cardiomyocytes are connected to each other through intercalated disks (ID), which are composed of a gap junction (GJ), adherens junction, and desmosome. Changes in the content as well as the subcellular localization of connexin43 (Cx43), the main component of the cardiac GJ, are reportedly involved in cardiac arrythmias and subsequent damage. Recently, the hippo-YAP signaling pathway, which links cellular physical status to cell proliferation, differentiation, and apoptosis, has been implicated in cardiac homeostasis under physiological as well as pathological conditions. This study was conducted to explore the possible involvement of junctional intercellular communication, mechanotransduction through cytoskeletal organization, and the hippo-YAP pathway in cardiac damage caused by direct exposure to ethanol. HL-1 murine atrial cardiac cells were used since these cells retain cardiac phenotypes through ID formation and subsequent synchronous contraction. Cells were exposed to 0.5–2% ethanol; significant apoptotic cell death was observed after exposure to 2% ethanol for 48 hours. A decrease in Cx43 levels was already observed after 3 hours exposure to 2% ethanol, suggesting a rapid degradation of this protein. Upon exposure to ethanol, Cx43 translocated into lysosomes. Cellular cytoskeletal organization was also dysregulated by ethanol, as demonstrated by the disruption of myofibrils and intermediate filaments. Coinciding with the loss of cell-cell adherence, decreased phosphorylation of YAP, a hippo pathway effector, was also observed in ethanol-treated cells. Taken together, the results provide evidence that cells exposed directly to ethanol show 1) impaired cell-cell adherence/communication, 2) decreased cellular mechanotransduction by the cytoskeleton, and 3) a suppressed hippo-YAP pathway. Suppression of hippo-YAP pathway signaling should be effective in maintaining cellular homeostasis in cardiomyocytes exposed to ethanol.
Highlights
Alcoholic cardiomyopathy, cardiac damage due to the chronic excessive drinking of alcoholic beverages, typically presents as idiopathic dilated cardiomyopathy including enlargement of the ventricle and resultant impairment of heart circulation [1, 2]
We first examined whether apoptosis is induced by exposing HL-1 cells to ethanol
We examined the protein levels of other connexins, Cx40 and Cx45, which have been shown expressing in HL-1 cells [25]
Summary
Cardiac damage due to the chronic excessive drinking of alcoholic beverages, typically presents as idiopathic dilated cardiomyopathy including enlargement of the ventricle and resultant impairment of heart circulation [1, 2]. Acute drinking of excessive alcoholic beverages causes severe cardiac damage, which includes cardiac arrhythmia, tissue injuries such as apoptosis, and ultimate heart failure [1]. The loss of cardiac function by acute alcohol intoxication results from the depression of nerve and pulmonary systems, direct ethanol toxicity on cardiomyocytes has been demonstrated in vitro to include contractile dysfunction, hypertrophic cell growth, and the apoptotic death of cardiomyocytes [3, 4]. Cardiomyocytes communicate electrically with each other by exchanging ions and small molecules through the GJ, as well as mechanically by transmitting actomyosin tension through the desmosome [5]. Cx43 turnover is tightly regulated through protein degradation systems such as ubiqutin-proteasome, endosome-lysosome, and autophagy [8]
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