Combined bisoprolol and trimetazidine ameliorate arsenic trioxide -induced acute myocardial injury in rats: targeting PI3K/GSK-3β/Nrf2/HO-1 and NF-κB/iNOS signaling pathways, inflammatory mediators and apoptosis

BACKGROUND: Arsenic-trioxide (ATO) is an effective therapy for acute promyelocytic leukemia. Unfortunately, its utility is hindered by the risk of myocardial injury. Both bisoprolol (BIS) and trimetazidine (TMZ) have various pharmacological features, including anti-oxidant, anti-inflammatory, and anti-apoptotic properties. AIM: The cardioprotective effects of BIS and TMZ were studied, and their mechanistic role in ameliorating ATO-induced myocardial injury. MATERIALS AND METHODS: Forty male Wistar rats were randomly allotted into five groups as follows: normal control group (received normal saline, orally), ATO group (7.5 mg/kg, orally), BIS (8 mg/kg, orally), TMZ (60 mg/kg, orally), and finally combination group (BIS+TMZ+ATO). Following 21 days, samples of serum and cardiac tissues were obtained to perform biochemical, molecular, and histopathological investigations. RESULTS: The present study showed that ATO caused myocardial injury evidenced by changes in serum biomarkers (Aspatate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin-1), electrolyte imbalance, and lipid profiles alongside histopathologic changes. In addition, ATO administration significantly elevated malondialdehyde, nicotinamide adenine dinucleotide phosphate hydrogen oxidase, myloperoxidase, total nitrite, inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1β, interleukin-6, 8-Hydroxy-2'-deoxyguanosine, nuclear factor NF-kappa-B p65 subunit, glycogen synthase kinase-3 beta, and caspase-3 expression contemporaneously with down-regulation of reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, heme oxygenase 1, nuclear factor erythroid 2-related factor 2, phosphatidylinositol-3 kinase, p-PI3K, and Bcl-2 expression. Interestingly, pretreatment with BIS and TMZ significantly reversed the detrimental effects of ATO-induced myocardial injury at both cellular and molecular levels. Otherwise, combining the two drugs displayed more enhancement than each drug alone. CONCLUSION: The present research depicted that BIS and TMZ have the potential to protect the heart and provide therapeutic benefits by preventing acute heart injury induced by ATO. This is achieved by reversing the redox-sensitive pathway, reducing inflammation, and inhibiting apoptosis.