Prevention And Treatment Of Doxorubicin-induced Cardiotoxicity In H9c2 Cardiomyocytes By Dipeptidyl-peptidase 3

Objective: To study the prevention and treatment of doxorubicin-induced cardiotoxicity in H9c2 cardiomyocytes by dipeptidyl-peptidase 3.Research methods: H9c2 rat cardiomyocytes were selected and allocated into four groups:a control group(CTL),a Doxorubicin group(DOX),a Doxorubicin and non-targeting si RNA group(si-NC+DOX),and a Doxorubicin and DPP3-targeting si RNA group(siDPP3+DOX).CCK8 assay was used to observe cell viability and determine DOX dosage.Cell morphology and number were observed using an inverted microscope.Western blot and real-time PCR analyses were conducted to measure the expression of DPP3,Nrf2,HO-1,and Keap1.The experiments were repeated three times or more,and statistical analysis was performed using one-way ANOVA.A statistically significant difference was defined as P < 0.05.Results: 1.DOX causes significant myocardial cell damage and alters its morphology and quantity in vitro.2.DOX downregulates Nrf2 and HO-1 expression levels in cardiomyocytes(P < 0.05),impairs the Nrf2-Keap1 signaling pathway’s normal function,and causes oxidative damage to cardiomyocytes(P < 0.05).3.Compared with control group,DOX up-regulates the expression level of DPP3 in myocardial cells in vitro(P <0.05).4.DPP3 knockdown exacerbates myocardial cell injury and further aggravates the changes in cell morphology and number induced by DOX.The expression levels of Nrf2 and HO-1 in H9c2 cells treated with si-DPP3 were significantly lower than those in the siNC group(P < 0.05),and the changes were more pronounced than those in the nontransfected group.Conclusion: DOX can reduce the expression levels of intracellular antioxidant enzymes Nrf2 and HO-1,resulting in oxidative damage to cardiomyocytes and subsequent cardiotoxicity.DPP3 is involved in mitigating oxidative damage to cardiomyocytes during DOX-induced cytotoxicity.The underlying mechanism may involve the Nrf2-Keap1 signaling pathway.