Abstract 18428: Implication of HDAC1/HDAC2 in Paracrine Protection of Mesenchymal Stem Cells Following Acute Myocardial Ischemia
INTRODUCTION: We have previously indicated that inhibition of histone deacetylase1 (HDAC1) or HDAC2 promoted cardiomyogenic potential of mesenchymal stem cells (MSCs). But little is known regarding implication of HDAC1 or HDAC2 in MSC-induced paracrine protection. We and others have shown that MSCs mediate their beneficial effects primarily via paracrine action. In this study, therefore, we hypothesize that MSCs with specific inhibition of HDAC1 or HDAC2 not only possess increased cardiomyogenesis, but are able to acutely improve cardiac function following ischemia/reperfusion (I/R).
METHODS: MSCs were isolated from bone marrow (femur/tibia) of C57BL mice, and transfected with siRNAs of scramble, HDAC1, or HDAC2. Conditioned medium (CM) was collected from these transfected MSCs. Cardiac I/R was performed in isolated mouse hearts via Langendorff. 1.5ml CM was infused immediately before ischemia. Heart tissue was studied for activation of STAT3 and caspase3. Data were analyzed with two-way ANOVA, p<0.05=statistically significant.
RESULTS: Decreased HDAC1 or HDAC2 expression was observed in HDAC1 or HDAC2 siRNA transfected MSCs (Figure A). Inhibition of HDAC1 or HDAC2 resulted in increased expression of cardiac α-MHC, troponin I, and troponin T. Infusion of CM from MSC transfected with HDAC1 siRNA or HDAC2 siRNA significantly improved myocardial function following acute I/R as did CM from the cells treated with scramble siRNA (Figure B). Increased activation of myocardial STAT3 (a pro-survival signaling) was noticed among CM-pretreated groups after I/R compared to media control, whereas active caspase3 was reduced in these groups (Figure C).
Conclusion: Our results represented initial evidence, showing that specific inhibition of HDAC1 or HDAC2 not only increased cardiomyogenesis of MSCs, but retained their paracrine protection following acute I/R. This study provides new understanding for modification of MSCs to optimize their therapeutic efficacy.
- © 2013 by American Heart Association, Inc.