Soluble neprilysin is associated with myocardial damage and systolic dysfunction in an animal model of doxorubicin-induced cardiotoxicity

INTRODUCTION: Anthracycline-induced cardiotoxicity (AIC) is a serious complication of chemotherapy, and there is a need for cost-effective biomarkers to enable risk stratification. Serum neprilysin (sNEP) has been investigated as a biomarker in various cardiovascular conditions, but its role in AIC has not been evaluated. METHODS: Twelve-week-old Sprague-Dawley rats received intraperitoneal doxorubicin (DOX) either as a single 20 mg/kg dose (acute model, n = 8), four weekly doses of 5 mg/kg (chronic model, n = 11), or saline (controls, n = 8 for each model). Echocardiography was performed at baseline and on the final study day. Blood and left ventricular (LV) tissue were collected within 24 h (acute model) or one week (chronic model) after the last injection. NEP protein and mRNA expression were measured in LV tissue, and sNEP concentrations were determined in serum. RESULTS: In the chronic AIC model, LV NEP protein expression was significantly reduced compared with controls (982.56 ± 90.57 vs. 1132.86 ± 132.30 ng/L, p < 0.05). In the acute model, sNEP levels showed a strong positive correlation with the severity of LV cardiomyocyte vacuolization (rs = 0.81, p < 0.05). In the chronic model, sNEP levels were strongly and negatively correlated with cardiac output (r = - 0.91, p < 0.05). CONCLUSIONS: Chronic DOX exposure reduces LV NEP protein expression. Elevated serum sNEP is associated with greater early cardiomyocyte injury, while in chronic AIC, it correlates with a more severe decline in cardiac output. These findings suggest sNEP may be a potential biomarker for AIC.