The Role of MKP-5 In Mitochondrial Protection against Doxorubicin-Induced Cardiotoxicity

Doxorubicin (DOX) is a highly effective chemotherapeutic drug used to treat various cancers. Unfortunately, the clinical application of DOX is limited by its cardiotoxic effects, which can result in heart failure in cancer patients. PURPOSE: This study aims to investigate whether MAP kinase phosphatase-5 (MKP-5) deficiency promotes mitochondrial protection against doxorubicin-Induced cardiotoxicity (DIC). METHODS: To determine the role of MKP-5 in DIC, DOX was administered intraperitoneally to wild-type (Mkp-5+/+) and MKP-5-deficient (Mkp-5-/-) mice. Following DOX administration, the survival rate was assessed, and transcription factors involved in mitochondrial biogenesis in cardiac muscle were analysed through qRT-PCR or immunoblotting. RESULTS: After a cumulative dose of 20 mg/kg, the survival rate was markedly reduced in Mkp-5+/+ mice, whereas it remained normal in Mkp-5-/- mice. After a cumulative dose of 15 mg/kg, transcription factors involved in mitochondrial biogenesis, including Pgc-1a and Tfam, were preserved in cardiac muscle of Mkp-5-/- mice, compared to Mkp-5+/+ mice. Furthermore, p53 protein expression was significantly increased in the cardiac muscle of Mkp-5-/- mice, compared to Mkp-5+/+ mice. CONCLUSION: Our findings suggest that MKP-deficiency may prevent DIC by facilitating mitochondria in cardiac muscle. Given the significant number of cancer patients and survivors facing long-term heart issues, our research suggests that targeting MKP-5 may represent new therapeutic avenues for cancer patients and survivors.