Boosting Thioredoxin-1 Protects Against Acetaminophen-Induced Cardiotoxicity

Abstract

Background: Although overdose-induced acute hepatic failure following acetaminophen (APAP) administration is well documented, clinical studies have also reported myocardial infarction, cardiac dysfunction, arrhythmias, pericarditis, and cardiac myocyte necrosis in APAP poisoning. As APAP overdose is associated with excessive reactive oxygen species (ROS) production and metabolism-mediated glutathione depletion, the cytosolic thioredoxin system (Trx-1/TrxR1/NADPH) may offer an alternative mechanism for cardioprotection. Although transgenic mice overexpressing thioredoxin-1 (Trx-1) are protected against doxorubicin/Adriamycin-induced cardiotoxicity, whether pharmacological enhancement of the cytosolic Trx system can mitigate APAP-induced cardiotoxicity and improve the therapeutic efficacy of chlorpromazine (CPZ) remains unclear. Methods: Cardiotoxicity was induced in wild-type C57BL/6 mice using APAP (400 mg/kg, i.p.). Expression of the Trx system was upregulated via chronic daily administration of low-dose epinephrine (EP, 0.2 mg/kg, s.c. for 14 days), and mice were subsequently treated with a subtoxic dose of CPZ (6 mg/kg, i.p.). Results: EP significantly upregulated the expression of Trx-1, thioredoxin-like protein 1 (Trx-L1), and thioredoxin reductase 1 (TrxR1) in cardiac tissue. Furthermore, EP attenuated APAP-induced acute cardiac injury, and its combination with CPZ additively amplified these cardioprotective effects. These findings were supported by the normalization of serum cardiac biomarkers (aspartate aminotransferase [AST], lactate dehydrogenase [LDH], and cardiac troponin I [cTnI]), reduction of oxidative stress (restoration of reduced glutathione [GSH], superoxide dismutase [SOD], and nuclear factor erythroid 2-related factor 2 [Nrf2]) and inflammatory markers (tumor necrosis factor-alpha [TNF-α]) in cardiac tissue, and preservation of normal myocardial histological architecture. Mechanistically, activation of the Trx system was accompanied by upregulation of β-arrestin-1 and cAMP response element-binding protein 1 (CREB1), indicating their involvement in Trx-mediated cardioprotection. Conclusion: Pharmacological enhancement of the cytosolic thioredoxin system protects against APAP-induced acute cardiac injury, and combining EP with CPZ exerts an additive cardioprotective effect.