Perturbation of microRNAs in Rat Heart during Chronic Doxorubicin Treatment

Abstract

Anti-cancer therapy based on anthracyclines (DNA intercalating Topoisomerase II inhibitors) is limited by adverse effects of these compounds on the cardiovascular system, ultimately causing heart failure. Despite extensive investigations into the effects of doxorubicin on the cardiovascular system, the molecular mechanisms of toxicity remain largely unknown. MicroRNAs are endogenously transcribed non-coding 22 nucleotide long RNAs that regulate gene expression by decreasing mRNA stability and translation and play key roles in cardiac physiology and pathologies. Increasing doses of doxorubicin, but not etoposide (a Topoisomerase II inhibitor devoid of cardiovascular toxicity), specifically induced the up-regulation of miR-208b, miR-216b, miR-215, miR-34c and miR-367 in rat hearts. Furthermore, the lowest dosing regime (1 mg/kg/week for 2 weeks) led to a detectable increase of miR-216b in the absence of histopathological findings or alteration of classical cardiac stress biomarkers. In silico microRNA target predictions suggested that a number of doxorubicin-responsive microRNAs may regulate mRNAs involved in cardiac tissue remodeling. In particular miR-34c was able to mediate the DOX-induced changes of Sipa1 mRNA (a mitogen-induced Rap/Ran GTPase activating protein) at the post-transcriptional level and in a seed sequence dependent manner. Our results show that integrated heart tissue microRNA and mRNA profiling can provide valuable early genomic biomarkers of drug-induced cardiac injury as well as novel mechanistic insight into the underlying molecular pathways.

Specific MicroRNAs comparisons in hypoxia and morphine preconditioning against hypoxia-reoxgenation injury with and without heart failure

“…17 miR-215, miR-216b, miR-208b and miR-34c are specifically dysregulated by chronic doxorubicin treatment in vivo and also in HEK-293 and rat myoblastic cells H9c2 [23];…”

Comparison of Cardiac Troponin I and T, Including the Evaluation of an Ultrasensitive Assay, as Indicators of Doxorubicin-induced Cardiotoxicity

“…The overall design and implementation of this chronic doxorubicin study in rats was part of a larger study performed by the Health and Environmental Sciences Institute (HESI) Technical Committee on Application of Genomics to Mechanism-Based Risk Assessment to evaluate potential association between gene expression data and mechanisms of cardiotoxicity. The results of this other research will be reported separately, although some investigative work on microRNA profiling was recently published (Vacchi-Suzzi et al 2012). …”

Early diagnosis of doxorubicin-induced cardiotoxicity:The miRNA way

“…Conversely, the choice of miR-423-5p, previously associated to heart failure [23], is less clear, since anthracycline-triggered cardiac dysfunction is usually observed late after treatment [24]. An additional good candidate for evaluation could be represented by miR-34, which was indicated as regulated by Dox from several groups, even in the plasma of rats [20,25,26]. Given the high novelty and potential clinical relevance of this kind of study, probably a screening of expression of circulating…”