Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α

Abstract

Doxorubicin (DOX)-based chemotherapy is widely used to treat malignant tumors; however, the cardiotoxicity induced by DOX restricts its clinical usage. A therapeutic dose of DOX can activate ubiquitin-proteasome system. However, whether and how ubiquitin-proteasome system brings out DOX-induced cardiotoxicity remains to be investigated. Here we conducted a proteomics analysis of a DOX-induced cardiotoxicity model to screen the potentially ubiquitination-related molecules. Dysregulated TRIM25 was found to contribute to the cardiotoxicity. In vivo and in vitro cardiotoxicity experiments revealed that TRIM25 ameliorated DOX-induced cardiotoxicity. Electron microscopy and endoplasmic reticulum stress markers revealed that TRIM25 mitigated endoplasmic reticulum stress and apoptosis in DOX-induced cardiomyocytes. Mechanistically, the Co-immunoprecipitation assays and CHX pulse-chase experiment determined that TRIM25 affected p85α stability and promoted its ubiquitination and degradation. This leads to increase of nuclear translocation of XBP-1s, which mitigates endoplasmic reticulum stress. These findings reveal that TRIM25 may have a therapeutic role for DOX-induced cardiotoxicity.

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

“…Favorable effects of exogenous apelin were also observed in male Wistar rats with heart failure that showed a partial recovery from fibrosis in the left ventricular myocardium and the aorta (Ouyang et al, 2019). In a recent study by Shen et al (2022), treatment of male C57/B6 mice with 20 mg/kg total cumulative DOX dose caused prominent fibrotic changes in hearts (Shen et al, 2022). Conversely, there was no evidence of cardiac fibrosis in our mouse model despite the higher cumulative DOX dose of 24 mg/kg.…”

Spock2 Functions as a Key Time-Series Gene of Endothelial Cells in Sepsis-Induced Cardiomyopathy

“…Heart rate (HR), left ventricular ejection fraction (LVEF), and fractional shortening (LVFS) were measured, as previously described. 12 All measurements were averaged for 3 consecutive cardiac cycles and were performed by an experienced technician who was blinded to the experimental group identities.…”

“…Heart sections (5 mm thick) were stained with hematoxylin and eosin (H&E) according to the previously described procedures. 12 Immunofluorescence staining was performed using anti-CD68 (28058-1-AP, 1:200; Proteintech), anti-CD31 (28083-1-AP, 1:500; Proteintech), and anti-Spock2 (orb158486, 1:200; Bioryt) antibodies. Images were analyzed using ImageJ software.…”