Purpose: Cardiac injury is a major cause of death in cancer survivors, and
biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EV) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury.Experimental Design: Using a mouse model of
doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed
proteomes, measured oxidized
protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content.Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EV) compared with saline-treated controls. DOX_EVs exhibited a higher level of
4-hydroxynonenal adducted
proteins, a lipid peroxidation product linked to DOX-induced
cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver
isoforms of
glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues.
Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with
cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac
troponin in the blood after DOX treatment, suggesting that PYGB is an early
indicator of cardiac injury.Conclusions: EVs containing PYGB are an early and sensitive
biomarker of cardiac injury. Clin
Cancer Res; 24(7); 1644-53. ©2017 AACRSee related commentary by Zhu and Gius, p. 1516.