Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury

Autor: Haining Zhu, Younsoo Bae, Daret K. St. Clair, Jing Chen, Emily V. Dressler, D. Allan Butterfield, Michael C. Alstott, Dustin Carroll, Chontida Yarana, Yanming Zhao, Luksana Chaiswing, Jeffrey A. Moscow, Teresa Noel
Rok vydání: 2017
Předmět:
0301 basic medicine
Male
Proteomics
Cancer Research
Proteome
030204 cardiovascular system & hematology
Pharmacology
medicine.disease_cause
Biochemistry
Lipid peroxidation
chemistry.chemical_compound
Mice
0302 clinical medicine
Myocyte
Medicine
Myocytes
Cardiac
030212 general & internal medicine
Brain
Anatomy
medicine.anatomical_structure
Oncology
Liver
030220 oncology & carcinogenesis
Biomarker (medicine)
Oxidation-Reduction
medicine.drug
Heart Diseases
Biology
Glycogen phosphorylase
03 medical and health sciences
Extracellular Vesicles
Physiology (medical)
Animals
Doxorubicin
Liquid biopsy
Muscle
Skeletal
Cardiotoxicity
Aldehydes
business.industry
Superoxide Dismutase
Cancer
Skeletal muscle
medicine.disease
Mice
Inbred C57BL
Disease Models
Animal
Kinetics
030104 developmental biology
Proteotoxicity
chemistry
Immunology
Lipid Peroxidation
business
Oxidative stress
Biomarkers
Zdroj: Clinical cancer research : an official journal of the American Association for Cancer Research. 24(7)
ISSN: 1557-3265
Popis: Significant advances in the efficacy of cancer therapy have been accompanied by an escalation in side effects that result from therapy-induced injury to normal tissues. Cardiac injury is a major cause of death in cancer survivors, but biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EVs) sort out oxidized proteins from tissues into the circulation as a compensatory mechanism for preventing cellular proteotoxicity. Thus, the protein contents of EVs released during the pre-degeneration stage reflects oxidative stress phenomenon that is occurring in the early damaged tissue. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury. Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we found a significant increase in circulating EVs (DOX_EVs) compared to 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 FDA- approved 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 are released prior to the rise of cardiac troponin (the current standard-of-care marker of cardiac injury) in the blood after DOX treatment, suggesting that PYGB is an earlier indicator of cardiac injury than conventional serum biomarkers. Thus, EVs containing PYGB serve as a liquid biopsy that is clinically attractive diagnostic biomarker for therapeutic interventions.
Databáze: OpenAIRE
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