7 research outputs found
MicroRNA-4732-3p Is Dysregulated in Breast Cancer Patients with Cardiotoxicity, and Its Therapeutic Delivery Protects the Heart from Doxorubicin-Induced Oxidative Stress in Rats
Anthracycline-induced cardiotoxicity is the most severe collateral effect of chemotherapy
originated by an excess of oxidative stress in cardiomyocytes that leads to cardiac dysfunction. We
assessed clinical data from patients with breast cancer receiving anthracyclines and searched for
discriminating microRNAs between patients that developed cardiotoxicity (cases) and those that did
not (controls), using RNA sequencing and regression analysis. Serum levels of 25 microRNAs were
differentially expressed in cases versus controls within the first year after anthracycline treatment,
as assessed by three different regression models (elastic net, Robinson and Smyth exact negative
binomial test and random forest). MiR-4732-3p was the only microRNA identified in all regression
models and was downregulated in patients that experienced cardiotoxicity. MiR-4732-3p was also
present in neonatal rat cardiomyocytes and cardiac fibroblasts and was modulated by anthracycline
treatment. A miR-4732-3p mimic was cardioprotective in cardiac and fibroblast cultures, following
doxorubicin challenge, in terms of cell viability and ROS levels. Notably, administration of the
miR-4732-3p mimic in doxorubicin-treated rats preserved cardiac function, normalized weight loss,
induced angiogenesis, and decreased apoptosis, interstitial fibrosis and cardiac myofibroblasts. At the
molecular level, miR-4732-3p regulated genes of TGFβ and Hippo signaling pathways. Overall, the
results indicate that miR-4732-3p is a novel biomarker of cardiotoxicity that has therapeutic potential
against anthracycline-induced heart damage