miR-21-5p as a potential biomarker of inflammatory infiltration in the heart upon acute drug-induced cardiac injury in rats

Investigation of genomic changes in cardiotoxicity can provide novel biomarkers and insights into molecular mechanisms of drug-induced cardiac injury (DICI). The main objective of this study was to identify and characterize dysregulated microRNAs (miRNAs) in the heart associated with cardiotoxicity. Wistar rats were dosed once with either isoproterenol (1.5 mg/kg, i.p), allylamine (100 mg/kg, p.o.) or the respective vehicle controls. Heart tissue was collected at 24 h, 48 h and 72 h post-drug administration and used for histopathological assessment, miRNA profiling, immunohistochemical analysis and in situ hybridization. Multiplex analysis of 68 miRNAs in the heart revealed a significant upregulation of several miRNAs (miR-19a-3p, miR-142-3p, miR-155-5p, miR-208b-3p, miR-21-5p) after isoproterenol and one miRNA (miR-21-5p) after allylamine administration. Localization of miR-21-5p was specific to inflammatory cell infiltrates in the heart after both treatments. Immunohistochemical analysis of Stat3, a known miR-21-5p regulator, also confirmed its upregulation in cardiomyocytes and inflammatory cell infiltrates. The toxicity signatures based on miRNA networks, identified in vivo, can potentially be used as mechanistic biomarkers as well as to study cardiotoxicity in vitro in order to develop sensitive tools for early hazard identification and risk assessment.