Maduramicin induces apoptosis and necrosis, and blocks autophagic flux in myocardial H9c2 cells.

Abstract

Maduramicin, a polyether ionophore antibiotic, is widely used as an anticoccidial agent in the poultry industry. It has been reported that maduramicin may cause heart and skeletal muscle cell damage, resulting in heart failure, skeletal muscle degeneration and even death in animals and humans, if improperly used. However, the molecular mechanism behind its capability to cause death of cardiac cells is not known. Here, we show that maduramicin induced apoptosis and necrosis in rat myocardial cells (H9c2). Maduramicin did not apparently upregulate the expression of pro-apoptotic proteins (e.g., BAD, BAK and BAX) or downregulate the expression of anti-apoptotic proteins (e.g. Bcl-2, Bcl-xL, Mcl-1 and survivin). Interestingly, maduramicin increased the expression of DR4 and TRAIL, activating caspases 8/3 and triggering cleavage of poly ADP ribose polymerase (PARP). In addition, maduramicin induced nuclear translocation of apoptosis inducing factor. Furthermore, maduramicin blocked autophagic flux, as evidenced by inducing accumulation of both LC3-II and p62/SQSTM1. Taken together, the above results suggest that maduramicin executes its toxicity in the myocardial cells at least by inducing caspase-dependent cell death through TRAIL/DR4-mediated extrinsic pathway and caspase-independent cell death by inducing apoptosis inducing factor nuclear translocation and blocking autophagic flux. Our findings provide a new insight into the molecular mechanism of maduramicin's toxicity in myocardial cells.

• Authors: Xin Chen, Long Chen, Shanxiang Jiang, Shile Huang
• Journal: Journal of applied toxicology : JAT (J Appl Toxicol) Vol. 38 Issue 3 Pg. 366-375 (03 2018) ISSN: 1099-1263 [Electronic] England
• PMID: 29047155 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 John Wiley & Sons, Ltd.

Chemical References

• Anti-Bacterial Agents
• Apoptosis Regulatory Proteins
• Autophagy-Related Proteins
• Lactones
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Tnfsf10 protein, rat
• maduramicin

Topics

• Animals
• Anti-Bacterial Agents (toxicity)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects)
• Autophagy-Related Proteins (metabolism)
• Cardiotoxicity
• Cell Line
• Lactones (toxicity)
• Myocytes, Cardiac (drug effects, pathology)
• Necrosis
• Rats
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)