Potential role of the apelin‐APJ pathway in sex‐related differential cardiotoxicity induced by doxorubicin in mice

Preclinical and clinical findings suggest sexual dimorphism in cardiotoxicity induced by a chemotherapeutic drug, doxorubicin (DOX). However, molecular alterations leading to sex‐related differential vulnerability of heart to DOX toxicity are not fully explored. In the present study, RNA sequencing in hearts of B6C3F1 mice indicated more differentially expressed genes in males than females (224 vs. 19; ≥1.5‐fold, False Discovery Rate [FDR] < 0.05) at 1 week after receiving 24 mg/kg total cumulative DOX dose that induced cardiac lesions only in males. Pathway analysis further revealed probable inactivation of cardiac apelin fibroblast signaling pathway (p = 0.00004) only in DOX‐treated male mice that showed ≥1.25‐fold downregulation in the transcript and protein levels of the apelin receptor, APJ. In hearts of DOX‐treated females, the transcript levels of apelin (1.24‐fold) and APJ (1.47‐fold) were significantly (p < 0.05) increased compared to saline‐treated controls. Sex‐related differential DOX effect was also observed on molecular targets downstream of the apelin‐APJ pathway in cardiac fibroblasts and cardiomyocytes. In cardiac fibroblasts, upregulation of Tgf‐β2, Ctgf, Sphk1, Serpine1, and Timp1 (fibrosis; FDR < 0.05) in DOX‐treated males and upregulation of only Tgf‐β2 and Timp1 (p < 0.05) in females suggested a greater DOX toxicity in hearts of males than females. Additionally, Ryr2 and Serca2 (calcium handling; FDR < 0.05) were downregulated in conjunction with 1.35‐fold upregulation of Casp12 (sarcoplasmic reticulum‐mediated apoptosis; FDR < 0.05) in DOX‐treated male mice. Drug effect on the transcript level of these genes was less severe in female hearts. Collectively, these data suggest a likely role of the apelin‐APJ axis in sex‐related differential DOX‐induced cardiotoxicity in our mouse model.