Plasma miR-208 as a useful biomarker for drug-induced cardiotoxicity in rats

• Published in: Journal of applied toxicology Vol. 35; no. 2; pp. 173 - 180
• Main Authors: Nishimura, Yoko, Kondo, Chiaki, Morikawa, Yuji, Tonomura, Yutaka, Torii, Mikinori, Yamate, Jyoji, Uehara, Takeki
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.02.2015; Wiley Subscription Services, Inc
• Subjects: Animals; biomarker; Biomarkers; Biomarkers - blood; cardiotoxicity; Cardiotoxicity - blood; Cardiotoxicity - etiology; Cardiotoxicity - pathology; Doxorubicin; Doxorubicin - toxicity; Elevated; Heart; Heart - drug effects; Isoproterenol; Isoproterenol - toxicity; Male; MicroRNAs - blood; miR-208; miRNA; Monitoring; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Myocardium - pathology; Oligonucleotide Array Sequence Analysis; Organs; Pharmacology; Plasma; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Ribonucleic acids; Side effects; Toxicity; troponin; Troponin - blood; miRNA; cardiotoxicity; troponin; biomarker; miR-208
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.3044

ABSTRACT Cardiotoxicity is one of the major safety concerns in drug development. Therefore, detecting and monitoring cardiotoxicity throughout preclinical and clinical studies is important for pharmaceutical companies. The present study was conducted in order to explore a plasma miRNA biomarker for cardiotoxicity in rats. As organ specificity is an important factor for a biomarker, we analyzed the miRNA microarray dataset in 55 organs/tissues in normal male rats. Based on this analysis, 5 miRNAs consisting of miR‐208 (heart‐specific), miR‐1, miR‐133a, miR‐133b (heart and skeletal muscle‐specific) and miR‐206 (skeletal muscle‐specific) were selected. Next, we evaluated the usefulness of those 5 miRNAs as circulating biomarkers in rats administered with single‐dose isoproterenol or doxorubicin. Plasma miR‐208 was consistently increased through 24 h after dosing in rats administered with isoproterenol, whereas plasma concentrations of cardiac troponin (cTn) showed transient elevation. In contrast, the plasma levels of miR‐1, miR‐133a, miR‐133a and miR‐206 were elevated after treatment with doxorubicin, probably as a result of skeletal muscle toxicity. Additionally, the plasma miR‐208 level was elevated even after repeat‐dose administration (once daily for 7 days) of isoproterenol under which the pathological condition proceeded to the sub‐chronic phase such as fibrosis. Thus, our data suggest that miR‐208 is a promising plasma biomarker for cardiotoxicity in rats. Monitoring of plasma miR‐208 levels in rats may lead to more accurate evaluation of cardiotoxicity in preclinical studies. Copyright © 2014 John Wiley & Sons, Ltd. The present study was conducted in order to explore a plasma miRNA biomarker for cardiotoxicity in rats. We selected candidate miRNAs by the analysis of the miRNA microarray dataset derived from comprehensive organs/tissues in normal rats, and confirmed their usefulness in drug‐induced rat cardiotoxicity. From the analysis, plasma miR‐208 showed the most sensitive and sustainable increase and it appears to be a promising biomarker for drug‐induced cardiotoxicity in rats.