Bosentan confers cardioprotection against cisplatin toxicity: Involvement of β-arrestin-linked ETA receptor signaling

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.