Abstract 14712: Exosomal Transfer of Hsf1 Prevents Apoptosis in Ischemic Myocytes by Chromatin Remodeling of Mir-34a
Background: We showed heat shocked Sca-1+ cells (HSSca-1+ cells) transplantation significantly reduced cardiomyocytes (CM) apoptosis and improved cardiac functions post myocardial infarction as compared to non-heat shocked Sca-1+ cells (non-HSSca-1+ cells). We hypothesized whether HSSca-1+ cells directs ischemic myocardium toward a prosurvival phenotype via paracrine behavior.
Methods and results: We demonstrated transplantation of HSSca-1+ cells leaded to upregulation of HSF1 and HSP70 and downregulation of miR-34a in left ventricles 4 days post transplanted with HSSca-1+ cells. ChIP-qPCR further revealed the repression of miR-34a in myocardium was associated with the chromatin remodeling on miR-34a promoter. The signaling events are very similar as we showed in HSSca-1+ cells (repression of miR-34a by HSF1 results in derepression of miR-34a target-HSP70 in HSSca-1+ cells), leading us to interrogate whether HSSca-1+ cells influence ischemic myocardium by paracrine behavior. Interestingly, we found HSF1 was significantly enriched in exosomes isolated from culture medium of HSSca-1+ cells (ExoHS) as compared to the ones from non-HSSca-1+ cells (Exonon-HS). To test whether ExoHS could rescue CM apoptosis, we administered ExoHS/Exonon-HS into the culture medium of neonatal CM respectively and incubated for 24 h then subjected the neonatal CM to OGD for 4 h. We found that CM incubated with ExoHS showed significantly reduced apoptosis as compared to Exonon-HS. Moreover, molecular analysis revealed administration of ExoHS significantly induced upregulation of HSF1 and HSP70, and downregulation of miR-34a and ChIP-qPCR showed decreased enrichment of H3K4me3, Pol II and increased enrichment of H3K27me3 in cardiomyocytes on miR-34a promoter.
Conclusions: HSSca-1+ cells direct ischemic myocardium toward a prosurvival phenotype possibly by transfer of exosomal transfer of HSF1, mediating alteration of chromatin structure of miR-34a.
- © 2013 by American Heart Association, Inc.