Compound glycyrrhizin tablets have induced Chronic cardiotoxicity in Sprague-Dawley rats by activating oxidative stress through the Keap1/Nrf2/HO-1 signaling pathway

Abstract

Abstract Introduction: The purpose of this study is to look into the mechanism of chronic cardiotoxicity induced by a long-term use of compound glycyrrhizin tablets (CGT). Materials and Methods: CGT was orally administered to SD rats. Then, the relative heart weight was measured, and the pathological changes of heart tissue were observed. Physiological indices were determined, including alanine aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase (CK), creatine kinase isoenzyme (CK-MB), brain natriuretic peptide (BNP), superoxide dismutase (SOD), and malondialdehyde (MDA). The levels of Na+-K+-ATPase and Ca2+-Mg2+-ATPasewere detected. The expressions of M-CK, BNP, Keap1, Nrf2, and HO-1 were assessed. Results: After several days of CGT treatment, the rats showed heavier relative heart weight and were found to have pathological changes in heart tissues. Moreover, the serum levels of LDH, AST, CK, CK-MB, and BNP were increased in the dose groups. The expression of M-CK was elevated in the middle-dose and high-dose groups, while the level of BNP showed an upward trend. The level of SOD was decreased, and the content of MDA was increased. The expressions of cytoplasma-Keap1 were increased in the middle-dose and high-dose groups, and the expression of nucleus-Nrf2 was reduced in all CGT groups, and the expression of HO-1 was decreased in the high-dose group. Conclusions: According to these results, we suggest that long-term and high-dose CGT administration is up-regulating Keap1, down-regulating nuclear-Nrf2 and HO-1, resulting in elevating the level of ROS and inducing cardiotoxicity in SD rats by activating the oxidative stress pathway.