Abstract
Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients. Therapeutic modulation of microRNA expression is emerging as a cardioprotective approach in several cardiovascular pathologies. MiR-34a increased in animals and patients exposed to anthracyclines and is involved in cardiac repair. In our previous study, we demonstrated beneficial effects of miR-34a silencing in rat cardiac cells exposed to doxorubicin (DOXO). The aim of the present work is to evaluate the potential cardioprotective properties of a specific antimiR-34a (Ant34a) in an experimental model of DOXO-induced cardiotoxicity. Results indicate that in our model systemic administration of Ant34a completely silences miR-34a myocardial expression and importantly attenuates DOXO-induced cardiac dysfunction. Ant34a systemic delivery in DOXO-treated rats triggers an upregulation of prosurvival miR-34a targets Bcl-2 and SIRT1 that mediate a reduction of DOXO-induced cardiac damage represented by myocardial apoptosis, senescence, fibrosis and inflammation. These findings suggest that miR-34a therapeutic inhibition may have clinical relevance to attenuate DOXO-induced toxicity in the heart of oncologic patients.
Highlights
Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients
The potential cardioprotective properties of miR-34a silencing were assessed in the well-known model of DOXO-induced cardiotoxicity[26,27,28,29,30,31]
Diastolic function was significantly deteriorated as evidenced by the increase of E Dec T and isovolumetric relaxation time (IVRT) parameters (Fig. 2a), measured following pulsed-wave Doppler, while systolic one evaluated by ejection fraction (EF) and fractional shortening (FS) did not show significant variations (Fig. 2b)
Summary
Cardiotoxicity remains a serious problem in anthracycline-treated oncologic patients. Ant34a systemic delivery in DOXO-treated rats triggers an upregulation of prosurvival miR-34a targets Bcl-2 and SIRT1 that mediate a reduction of DOXO-induced cardiac damage represented by myocardial apoptosis, senescence, fibrosis and inflammation. These findings suggest that miR-34a therapeutic inhibition may have clinical relevance to attenuate DOXO-induced toxicity in the heart of oncologic patients. Cells makes its inhibition an attractive therapeutic perspective These findings prompted us to assess the potential cardioprotective effect of Ant34a in vivo. In the present work, we evaluated the consequences of miR-34a silencing on DOXO-related pathways and importantly on cardiac function in a rat model of DOXOinduced cardiotoxicity
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