Maduramicin, a polyether
ionophore antibiotic used as an anticoccidial agent in poultry industry, has been reported to be toxic to animals and humans if improperly used or by accident, resulting in
heart failure, skeletal muscle degeneration and even death. However, the molecular mechanism underlying its
cardiotoxicity remains elusive.
Mitogen activated protein kinases (MAPKs) and
protein phosphatases signaling pathways have been documented to be involved in the cell survival regulation. The present study was set to investigate the role of above pathways in
maduramicin-induced myocardial cytotoxicity. Here we observed that
maduramicin inhibited cell proliferation and reduced cell viability in H9c2 cells. Furthermore, we found that
maduramicin suppressed
extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in a concentration-dependent manner. Ectopic expression of constitutively active MKK1 partially prevented the cytotoxicity of
maduramicin. Moreover, we showed that
maduramicin concentration-dependently activated
protein phosphatase 2A (PP2A) by decreasing its phosphorylation and increasing its methylation. Inhibition of PP2A with
okadaic acid attenuated
maduramicin's toxicity. Overexpression of dominant negative PP2A partially rescued cells from
maduramicin-inhibited ERK1/2 contributing to its cytotoxicity. The results indicate that
maduramicin activates PP2A and consequently inhibits ERK1/2, leading to cytotoxicity in H9c2 cells. Our data suggest that manipulation of PP2A-ERK1/2 pathway may be a potential approach to prevent
maduramicin-induced
cardiotoxicity.