September 11, 2019Open Access

miR-146a attenuates apoptosis and modulates autophagy by targeting TAF9b/P53 pathway in doxorubicin-induced cardiotoxicity

Structured PICO

Does miR-146a attenuate doxorubicin-induced cardiotoxicity in cardiomyocytes and mouse models?

Population

Human AC16 cardiomyocyte cell line and male wild-type and miR-146a-/- C57BL/6 mice weighing 18-22 g

Intervention

miR-146a overexpression (in vitro) or deficiency (in vivo) during doxorubicin treatment (in vitro: 0.5 μM for 48h; in vivo: i.p. 5 mg/kg/week for 4 weeks)

Comparator

Scrambled mimics/inhibitors (in vitro) or wild-type mice / saline treatment (in vivo)

Outcome

Cardiotoxicity measured by apoptosis, autophagy markers, cell viability, and cardiac function (ejection fraction and fractional shortening)surrogate

miR-146a protects against doxorubicin-induced cardiotoxicity by targeting the TAF9b/P53 pathway to reduce apoptosis and modulate autophagy.

Abstract

Clinical therapy of doxorubicin (DOX) is limited due to its cardiotoxicity. miR-146a was proved as a protective factor in many cardiovascular diseases, but its role in chronic DOX-induced cardiotoxicity is unclear. The objective of this study was to demonstrate the role of miR-146a in low-dose long-term DOX-induced cardiotoxicity. Experiments have shown that DOX intervention caused a dose-dependent and time-dependent cardiotoxicity involving the increased of apoptosis and dysregulation of autophagy. The cardiotoxicity was inhibited by overexpressed miR-146a and was more severe when miR-146a was downgraded. Further research proved that miR-146a targeted TATA-binding protein (TBP) associated factor 9b (TAF9b), a coactivator and stabilizer of P53, indirectly destroyed the stability of P53, thereby inhibiting apoptosis and improving autophagy in cardiomyocytes. Besides, miR-146a knockout mice were used for in vivo validation. In the DOX-induced model, miR-146a deficiency made it worse whether in cardiac function, cardiomyocyte apoptosis or basal level of autophagy, than wild-type. In conclusion, miR-146a partially reversed the DOX-induced cardiotoxicity by targeting TAF9b/P53 pathway to attenuate apoptosis and adjust autophagy levels.

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