Doxorubicin-induced Cardiotoxicity is Propagated by Paracrine Signaling through Small Extracellular Vesicles

Area of Science:

• Oncology
• Cardiology
• Molecular Biology

Background:

• Cardiovascular disease (CVD) is a leading cause of death globally.
• Doxorubicin (DOX) is a vital chemotherapy for breast cancer but can induce cardiotoxicity.
• The mechanisms underlying DOX-induced cardiotoxicity remain unclear.

Purpose of the Study:

• To investigate how DOX affects cardiac cell function and paracrine signaling.
• To determine if altered paracrine factors can induce cardiotoxicity in healthy cells.
• To explore the potential of plasma extracellular vesicle microRNAs (EV miRNAs) as biomarkers for DOX-induced cardiotoxicity.

Main Methods:

• Cardiac cells were treated with DOX to analyze changes in function and paracrine signaling.
• Healthy cells were exposed to altered paracrine agents to assess cardiotoxicity.
• Plasma EV miRNA profiles of patients were analyzed and correlated with DOX-cardiotoxicity risk.
• Bioinformatic pathway analysis was performed on distinguishing miRNAs.

Main Results:

• DOX treatment alters cardiac cell function and paracrine signaling profiles.
• Altered paracrine agents recapitulated DOX-induced cardiotoxicity in vitro.
• Plasma EV miRNA signatures distinguished patients by DOX-cardiotoxicity risk.
• Identified miRNAs are linked to cardiac homeostasis and cardiotoxicity pathways.

Conclusions:

• DOX-induced cardiotoxicity may be propagated by altered paracrine signaling, including EV miRNAs.
• Plasma EV miRNAs show promise as noninvasive biomarkers for early risk stratification.
• Targeting specific miRNA pathways could lead to novel cardioprotective strategies in cancer patients.