Based on Activation of p62-Keap1-Nrf2 Pathway, Hesperidin Protects Arsenic-Trioxide-Induced Cardiotoxicity in Mice.

Yuxin Jia,Jing Li,Mingdong Si,Hongfang Wang,Panpan Liu,Li Chu,Yanyu Jin,Donglai Ma

doi:10.3389/fphar.2021.758670

Abstract

Background: Hesperidin (HES) is a flavonoid glycoside found in the tangerine peel and has antioxidant properties. Arsenic trioxide (ATO) is an anti-tumour drug; however, its serious cardiotoxicity limits its clinical application. In addition, the protection of HES against ATO-induced cardiotoxicity has not been explored. Objective: The study aims to investigate and identify the underlying effect and mechanism of HES on ATO-induced cardiotoxicity. Methods: Fifty mice were randomly assigned to five groups. Mice were orally given HES:100 or 300 mg/kg/day concurrently and given ATO intraperitoneal injections: 7.5 mg/kg/day for 1 week. Blood and heart tissues were collected for examination. Evaluated in serum was the levels of creatine kinase (CK), lactate dehydrogenase (LDH) and cardiac troponin I (cTnI). In addition, evaluated in heart tissues were the levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), catalase (CAT), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, cleaved-Caspase-3, p62, Kelch-like ECH-associated protein 1 (Keap1), and nuclear factor erythroid 2-related factor 2 (Nrf2). The heart tissues were also examined for histopathology and mitochondrial ultrastructure. Results: Compared with the ATO group, the HES treatment groups reduced the levels of CK, LDH, cTnI, ROS, MDA, TNF-α, IL-6, Bax, Caspase-3, cleaved-Caspase-3 and Keap1 and enhanced the levels of SOD, GSH, CAT, Bcl-2, p62 and Nrf2. Conclusions: The results demonstrate that HES protects against ATO-induced cardiotoxicity, through inhibiting oxidative stress, and subsequent inflammation and apoptosis. The underlying results are closely related to the regulation of the p62-Keap1-Nrf2 signalling pathway.

Highlights

Acute promyelocytic leukaemia (APL) is a distinct type of acute myeloid leukaemia, which has a “rapid downhill course” and is characterised by a severe bleeding tendency (Hillestad, 1957)
General observations showed that the average daily intake of water and diet in the Arsenic trioxide (ATO) group was significantly different from that of the Control group (CONT) group (p < 0.01; Table 1)
At the end of the experiment, the average body weight of mice in the ATO group significantly reduced compared with the CONT, HESL, and HESH groups (p < 0.05 or p < 0.01)

Summary

Introduction

Acute promyelocytic leukaemia (APL) is a distinct type of acute myeloid leukaemia, which has a “rapid downhill course” and is characterised by a severe bleeding tendency (Hillestad, 1957). The main cardiotoxicity manifestations are QT prolongation, torsades de pointes, and sudden cardiac death (Barbey and Soignet, 2001; Unnikrishnan et al, 2001; Westervelt et al, 2001). These events may increase the prevalence of cardiovascular disease in APL patients who have been offered ATO therapy. It is important to explore the cardiac toxicity associated with ATO therapy and seek for appropriate attenuating drugs to improve its clinical application. Arsenic trioxide (ATO) is an anti-tumour drug; its serious cardiotoxicity limits its clinical application. The protection of HES against ATO-induced cardiotoxicity has not been explored

Methods

Results

Conclusion