Combined Usage of Trimetazidine With 3-Bromopyruvate May Lead to Cardiotoxicity by Activating Oxidative Stress and Apoptosis in Rats

Abstract

The energy used by the heart is generated mainly by the metabolism of fatty acids and glucose. Trimetazidine (TMZ) inhibits fatty acid metabolism and is used for the treatment of heart diseases such as heart failure. 3-Bromopyruvate (3-BrPA) can suppress glucose metabolism, and it is considered a promising candidate agent for tumor therapy. Because TMZ and 3-BrPA can separately inhibit the 2 main cardiac energy sources, it is necessary to investigate the effects of 3-BrPA combined with TMZ on the heart. Forty male Wistar rats were randomly divided into 4 groups: a control group, a TMZ group, a 3-BrPA group, and a 3-BrPA + TMZ group. Weight was recorded every day, and echocardiography was performed 14 days later. Heart function, the levels of adenosine triphosphate, oxidative stress-related factors (ROS, glutathione, oxidized glutathione, malondialdehyde, superoxide dismutase and total antioxidant capacity), and apoptosis in heart tissues were assessed to evaluate the effects of 3-BrPA and TMZ on the heart. In our study, no obvious changes occurred in the 3-BrPA group or the TMZ group compared with the control group. The combination of 3-BrPA and TMZ worsened heart function, decreased adenosine triphosphate levels, and increased oxidative stress and myocardial apoptosis. In conclusion, 3-BrPA and TMZ are not recommended for concurrent use.

Fatty acid metabolism disorders and potential therapeutic traditional Chinese medicines in cardiovascular diseases

“…Furthermore, increased fatty acid oxidation caused by acetyl‐CoA carboxylase 2 (ACC2) knockout can inhibit the development of cardiac hypertrophy (Choi et al, 2016). On the other hand, some fatty acid oxidation inhibitors (trimetazidine, etomoxir, perhexiline) showed beneficial effects on cardiac efficiency and have been used to treat heart failure in clinics (George et al, 2016; Nabben et al, 2014; Zheng et al, 2021). Notably, the beneficial effect of fatty acid oxidation inhibitors was accompanied by an increased glucose oxidation level, which has been regarded as the biggest contributor against heart failure (Lopaschuk et al, 2021).…”

Trimetazidine Attenuates Ischemia/Reperfusion-Induced Myocardial Ferroptosis by Modulating the Sirt3/Nrf2-GSH System and Reducing Mitochondrial Oxidative Stress

“…The hotspots of cell death in cardiovascular eld principally focus on apoptosis, pyroptosis, mitochondrial-mediated cell death, autophagy, and ferroptosis [16]. It has been indicated that TMZ is apt to restrain apoptosis in ischemia/reperfusion (I/R) and diabetic cardiomyopathy models [17][18][19]. And it can also affect pyroptosis by targeting Gasdermin D (GSDMD) and facilitating neutrophil migration [20,21].…”