Bosentan confers cardioprotection against cisplatin toxicity: Involvement of β-arrestin-linked ETA receptor signaling
Issued Date
2026-08-01
Resource Type
ISSN
00062952
eISSN
18732968
Scopus ID
2-s2.0-105039198723
Pubmed ID
42069228
Journal Title
Biochemical Pharmacology
Volume
250
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biochemical Pharmacology Vol.250 (2026)
Suggested Citation
Khine H.E.E., Mangmool S., Parichatikanond W. Bosentan confers cardioprotection against cisplatin toxicity: Involvement of β-arrestin-linked ETA receptor signaling. Biochemical Pharmacology Vol.250 (2026). doi:10.1016/j.bcp.2026.118027 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/116859
Title
Bosentan confers cardioprotection against cisplatin toxicity: Involvement of β-arrestin-linked ETA receptor signaling
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Abstract
The endothelin system, primarily through activation of the endothelin A (ET<inf>A</inf>) receptor, mediates vasoconstriction and triggers inflammatory and proliferative responses, positioning it as a key mediator and promising therapeutic target in cardiovascular injury. Bosentan, a dual ET<inf>A</inf>/ET<inf>B</inf> receptor antagonist, has been reported to act as a biased ligand at the ET<inf>A</inf> receptor. This study investigated whether bosentan protects H9c2 cardiomyoblasts against cisplatin-induced cardiotoxicity by preferentially modulating β-arrestin-related signaling of ET<inf>A</inf> receptor. Bosentan treatment suppressed cellular injury by attenuating reactive oxygen species (ROS) production, early apoptosis, and caspase-3/7 activity following cisplatin exposure. Bosentan preserved mitochondrial function by improving cellular respiration and glycolysis, as well as upregulating mitochondrial regulators OPA1 and ATP5A and anti-apoptotic BCL2, while downregulating mitochondrial fission-related DNM1 and pro-apoptotic BAX. Co-treatment with endothelin-1 (ET-1) synergistically aggravated cisplatin-induced cellular injury and diminished bosentan-mediated cardioprotection, supporting the involvement of ET receptors. ET<inf>A</inf> receptor blockade (BQ-123) enhanced bosentan-mediated protection more effectively than ET<inf>B</inf> receptor inhibition (BQ-788), suggesting ET<inf>A</inf> receptor dominance. Inhibition of β-arrestin (barbadin) reduced bosentan's efficacy to a greater extent than G<inf>αq</inf> protein inhibition (FR900359), highlighting a greater contribution of β-arrestin-mediated pathways. In addition, ERK1/2 and PI3K/AKT inhibition each impaired bosentan-enhanced pro-survival response, indicating the parallel involvement of both survival cascades. Although bosentan antagonizes both ET<inf>A</inf> and ET<inf>B</inf> receptors and modulates β-arrestin and G<inf>αq</inf> signaling, its protective effect appears primarily mediated by ET<inf>A</inf> receptor antagonism and β-arrestin-linked pro-survival signaling. This potential mechanism of bosentan may provide a basis for further investigation into therapeutic strategies for chemotherapy-induced cardiotoxicity.