A potential cardioprotective role of epigenetic repression in long-term cardiotoxicity of anthracyclines

Benay Eksi (Heidelberg)1, D. Finke (Heidelberg)2, V. Sunder (Heidelberg)1, J. Schahn (Heidelberg)1, M. Valadan (Heidelberg)1, N. Frey (Heidelberg)2, L. H. Lehmann (Heidelberg)2

1Universitätsklinikum Heidelberg Innere Medizin VIII, Institut für Experimentelle Kardiologie Heidelberg, Deutschland; 2Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland


Cancer therapy-associated cardiotoxicity often results in heart failure. The topoisomerase 2 (top2b) inhibitor Doxorubicin (DOX) is effective in treating cancer but associated with cardiotoxicity which can even manifest years after exposure. Top2b is the predominant isoform in cardiomyocytes and cardiomyocyte-specific deletion of top2b protects from DOX-induced cardiomyopathy. However, the exact pathological mechanism how DOX leads to cardiotoxicity is unknown.
In preliminary work it was found, that most promoters of poised top2b-bound genes overlapped with binding sites for the transcription factor MEF2 (myocyte enhancer factor 2). Since MEF2-dependent genes are crucial for pathological cardiac remodelling, we hypothesized that MEF2 inhibition might be cardioprotective. The FDA-approved pan HDAC-inhibitor SAHA lead to an accumulation of class II HDACs, accompanied by a possibly HDAC4-mediated inhibition of MEF2-transcriptional activity.
To prove the accumulation of HDAC4 in the nucleus after SAHA treatment, the localization of HDAC4 was investigated by overexpression with an HDAC4-AV and detection by Immunostaining in DOX/SAHA treated neonatal rat cardiomyocytes.
In a long-term in-vivo model in mice DOX-treated mice showed a reduction in left ventricular ejection fraction compared to SAHA co-treatment (Control 50.3 ± 3.1%, n=12 vs. DOX 43.0 ± 3.4%, n=12; p<0.05; vs. DOX+SAHA 50.6 ± 7.4%, n=11, p>0.05). DOX-dependent dysregulation of pathological genes such as myh7 was blunted in SAHA treated animals.
To prove the importance of HDAC4 in MEF2 inhibition, the in-vivo model in mice was repeated and SAHA was replaced by the selective HDAC class II inhibitor TMP195. The results reveal no improvement of DOX-dependent cardiac dysfunction in the co-treatment with TMP195 (Control 49.1 ± 7.8%, n=12 vs. DOX 40.8 ± 4.8%, n=10, p<0.05; vs. DOX+TMP195 37.1 ± 6.2%, n=6, p<0.05). MEF2 target genes such as myh7 were not reversed in the DOX+TMP195 group. Furthermore, a significant reduction in the survival rate was evident in the co-treatment with TMP195.
These results indicate a potential HDAC4-mediated MEF2 inhibition by SAHA that might be cardioprotective in DOX-induced cardiotoxicity.

Diese Seite teilen