Abstract 323: MicroRNA208a Silencing Attenuates Doxorubicin Induced Cardiac Toxicity and Dysfunction
Aims: Salvaging GATA4 expression mitigates doxorubicin-induced myocyte apoptosis and cardiac dysfunction. We investigated if therapeutic silencing of miR-208a, a heart specific microRNA known to target GATA4, could attenuate doxorubicin-induced myocyte apoptosis and improve heart function.
Methods: Eight weeks old female Balb/C mice were randomly assigned to Sham, antagomir and Control groups. Antagomir group mice were pre-treated with 50nmols of miR-208a antagomir 4 days prior to giving doxorubicin. At day 0, control and antagomir group got 20mg/kg of doxorubicin while sham mice received phosphate buffered solution. Echocardiography was done at day 7, after which animals were sacrificed, and hearts assessed for apoptosis and expression of miR-208a, GATA4 and Bcl-2 by quantitative PCR.
Results: Doxorubicin significantly upregulated miR-208a P=0.008 , downregulated GATA4 P=0.025 , and increased myocyte apoptosis P=0.001. Therapeutic silencing of miR-208a mitigated the doxorubicin-induced increase in miR-208a, P= 0.003 and salvaged GATA4 expression, with noted increase in Bcl-2 levels compared to controls, P=0.033. Doxorubicin significantly increased cardiomyocyte apoptosis P= 0.001, and this effect was attenuated by pretreatment with miR-208a antagomir, P=0.002 (Figure 1A and B). Doxorubicin also caused significant cardiac dysfunction, P=0.005, while antagomir treatment attenuated doxorubicin-induced cardiac dysfunction as assessed by fractional shortening P=0.011 (Figure 1Cand D)
Conclusion: Therapeutic silencing of miR-208a salvages GATA4 and attenuates doxorubicin-induced myocyte apoptosis with subsequent improvement in cardiac function.
Author Disclosures: H. Tony: None. Q. Zeng: None. K. Yu: None.
- © 2015 by American Heart Association, Inc.