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

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.

Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients

“…In agreement with our findings, upregulation of the muscle-specific miR-1 and -133b in plasma was also reported after DOX administration in an animal model [5], while no significant changes were observed in mice hearts [4, 9]. Taken together, the maintaining of miR-1 levels in the heart and its progressive increase in plasma suggest an active release of miR-1 from the heart that is consistent with the increase of cardiomyocyte vacuolation reported after DOX treatment [4, 9].…”

“…The data presented in this study confirm previous reports showing that DOX treatment can perturb the expression of cardiac-related miRNAs [4, 5, 9]. Indeed, very few studies have evaluated miRNA expression patterns during DOX-induced cardiotoxicity, concentrating essentially on experimental approaches in mice or cell culture.…”

“…Interestingly, miR-208a (heart-specific miRNA) [17] and -208b were undetected in this study, although previously published studies have suggested them as new biomarkers of myocardial injury following myocardial infarction [18, 19] or isoproterenol use [5, 20, 21]. This discrepancy may be a result of a differential response of the cardiomyocytes to DOX stimuli.…”

“…During the last decade, these molecules garnered much attention for their potential as promising new biomarkers for a wide range of diseases with the benefits of both tissue and disease-specific expression signatures and high stability in body fluids [3]. Recently, some circulating miRNAs such as miR-1, -146a, -133b, -208a, -208b and -423-5p have been suggested as earlier biomarkers of myocardial injury, heart failure and/or drug-induced cardiotoxicity [4, 5]. However, until now, the potential of these circulating miRNAs as biomarkers of DOX-induced cardiotoxicity in a clinical setting has not been assessed.…”

Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis Through miR-3546/SOX4/Survivin Axis in Rat Thy-1 Nephritis

“…Based on these results, miR-3546 was selected to further determine its effect on sublytic C5b-9-triggered GMC apoptosis and the related regulatory mechanism. Notably, miR-3546 belongs to miR-208 family, and though several documents have pointed out that miR-208 has regulatory role in myocardial injury [42][43][44], there has not been any report about the function of miR-3546.…”