Modulation of ET1/NF-κB/IL-6/STAT-4/AP-1 pathway by ambrisentan alleviates isoprenaline-induced myocardial injury

Abstract

BACKGROUND: Myocardial injury stands as the foremost contributing factor in raising morbidity and mortality within the realm of cardiac diseases worldwide. Nowadays, there is no available treatment to completely rescue the myocardium. Thus, we aimed to study the possible role of ambrisentan (AMB) in experimentally induced myocardial damage using a highly toxic dose of isoprenaline (ISO) (150 mg/kg). METHODOLOGY: Rats were randomly divided into five groups: control, ISO given groups, which were administered alone or in combination with AMB in three different doses (10, 20, and 30 mg/kg/day). RESULTS: It was revealed that ISO administration could induce heart injury as confirmed by significant elevations of the cardiac enzymes, including lactate dehydrogenase (LDH), troponin I, and creatine kinase-MB (CK-MB). In addition, there are disturbed oxidative stress parameters in the form of a significant increase of malondialdehyde (MDA) but significant decreases of reduced glutathione (GSH) and total antioxidant capacity (TAC) with toxic histopathological changes and up-regulation of endothelin-1 (ET-1)/nuclear factor kappa B (NF-κB)/interleukin-6 (IL-6)/signal transducer and activator of transcription-4 (STAT-4)/activator protein-1 (AP-1) pathway. However, co-administration of AMB could ameliorate ISO-induced biochemical and histological changes. CONCLUSION: We concluded that AMB successfully diminished ISO-induced injury likely due to its main pharmacological action of selective inhibition on ET1A receptor, modulation of ET1/NF-κB/IL-6/STAT-4/AP-1 signaling pathways with anti-inflammatory, anti-apoptotic, and antioxidant properties.