Cardioprotective effects of miR-34a silencing in a rat model of doxorubicin toxicity

Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients. Therapeuticmodulation of microRNA expression is emerging as a cardioprotective approach in severalcardiovascular pathologies. MiR-34a increased in animals and patients exposed to anthracyclinesand is involved in cardiac repair. In our previous study, we demonstrated benefcial efects of miR-34asilencing in rat cardiac cells exposed to doxorubicin (DOXO). The aim of the present work is to evaluatethe potential cardioprotective properties of a specifc antimiR-34a (Ant34a) in an experimentalmodel of DOXO-induced cardiotoxicity. Results indicate that in our model systemic administrationof Ant34a completely silences miR-34a myocardial expression and importantly attenuates DOXO-induced cardiac dysfunction. Ant34a systemic delivery in DOXO-treated rats triggers an upregulationof prosurvival miR-34a targets Bcl-2 and SIRT1 that mediate a reduction of DOXO-induced cardiacdamage represented by myocardial apoptosis, senescence, fbrosis and infammation. These fndingssuggest that miR-34a therapeutic inhibition may have clinical relevance to attenuate DOXO-inducedtoxicity in the heart of oncologic patients.