Central Illustration.

Dose- and Time-Dependent Doxorubicin-Induced Cardiovascular Toxicity Is Inhibited by a GPCR Prokineticin Receptor-1 Signaling

We unraveled dose- and time-dependent molecular and cellular signatures of an anthracycline-mediated cardiotoxicity. Doxorubicin (DOX) at low dose (top left) has no effect on apoptosis or reactive oxygen species (ROS) accumulation in cardiomyocytes, whereas it reduces epicardium-derived progenitor cell (EDPC) plasticity and endothelial cell tube formation (in vitro angiogenesis). A medium dose of DOX (top middle) promotes apoptosis in all cardiac cells. However, a brief exposure of cardiomyocytes to a high dose of DOX (top right) inhibits the detoxification system via stabilizing nuclear factor erythroid-derived 2-like 2 (NRF2) in the cytoplasm, resulting in ROS accumulation. Chronic DOX cardiotoxicity in mice (bottom left) induces mortality with heart failure with reduced ejection fraction (HFrEF), diastolic dysfunction, and adverse cardiac remodeling, whereas acute DOX cardiotoxicity (bottom right) promotes diastolic volume declines. Prokineticin receptor 1 (PKR1) activation by a ligand (IS20) mitigates these detrimental effects of DOX in vitro and in vivo without altering its antitumoral effect.