Abstract 9534: Expression of Heme Oxygenase-1 in Cardiac Stem Cells Enhances the Efficacy of Cell Therapy for Attenuating Left Ventricular Dysfunction and Remodeling After Myocardial Infarction
Although transplantation of cardiac stem cells (CSCs) improves LV function and structure after myocardial infarction (MI), this salubrious effect is limited by early massive CSC loss due to apoptosis. Heme oxygenase-1 (HO-1) is known to exert potent antiapoptotic and cytoprotective effects. Thus, we hypothesized that expression of HO-1 in CSCs will enhance their survival and reparative ability. To test this hypothesis, lin-/c-kit+ CSCs were isolated and expanded from wild-type (WT), HO-1 transgenic (TG) or knockout (KO) mice. HO-1 protein overexpression in HO-1TG CSCs (confirmed by FACS and immunoblotting) was mild (3-fold greater than WT CSCs). Mice underwent a 60-minute coronary occlusion followed by reperfusion; 48 h later, they received intramyocardial injection of vehicle or WT, HO-1TG or HO-1KO CSCs (105 CSCs/heart). Sham mice underwent 1-hour open-chest state with no intervention. At 35 days post-MI, both WT and HO-1TG CSC transplantation resulted in alleviation of LV dysfunction and remodeling compared with vehicle group; however, the magnitude of the beneficial effects of HO-1TG CSCs was significantly greater than that of WT CSCs. Compared with WT CSCs, transplantation of HO-1TG CSCs resulted in a greater improvement in global and regional LV function (assessed by two independent methods - echocardiography and conductance catheter) and a greater increase in viable myocardial tissue in the risk region, suggesting increased formation of new cardiomyocytes (Fig). In contrast, transplantation of HO-1KO CSCs failed to produce any LV structural or functional benefits. These results indicate, for the first time, that even a mild increase in HO-1 promotes CSC competence and that expression of HO-1 is a powerful strategy to enhance the cardiac reparative actions of CSCs in limiting LV dysfunction and remodeling post-MI. The data provide a potential therapeutic approach for promoting myocardial regeneration via modification of CSCs with cytoprotective genes.
- © 2012 by American Heart Association, Inc.