Abstract 3882: Overexpression Of Insulin-like Growth Factor-II In Expanded Endothelial Progenitor Cells Improves Left Ventricular Function In Experimental Myocardial Infarction
Background: Insulin-like growth factors are mediators of growth hormone-induced metabolic and anabolic actions, but also regulate cell growth, differentiation and apoptosis by activation of IGF-I receptor. Moreover, IGF-II showed mitogenic signals through a high affinity interaction with isoform A of the insulin receptor. Since endothelial progenitor cells improve myocardial function after acute myocardial infarction we sought to investigate whether overexpression of IGF-II in expanded endothelial progenitor cells (eEPCs) further contributes to improvement in left ventricular function after myocardial infarction.
Methods and Results: CD34+ cells from cord blood were isolated using immunomagnetic beads and cultured in endothelial cell medium to obtain eEPC. Early passage eEPCs were transduced ex vivo by a retroviral vector expression of IGF-II (eEPC-IGF-II) or empty vector and expanded. Expression levels were confirmed by RT-PCR. Athymic, nude rats were thoracotomized and ligation of the left anterior descending coronary artery was performed for 30 minutes before reperfusion was initiated. Vector only transduced eEPC or eEPC-IGF-II cells were injected immediately after reperfusion in the border of the infarct zone and serial echocardiographic measurements were performed to analyze left ventricular ejection fraction. Two weeks after myocardial infarction animals were sacrificed. Transplantation of eEPCs improved left ventricular function after experimental myocardial infarction from 44 β 0.9 to 52 β 0.6% at 2 weeks (p<0.05, n=10 –12). Overexpression of IGF-II further improved left ventricular ejection fraction to 54 β 0.7 % (p<0.05, n=10 –12). In vitro experiments revealed that IGF-II dose-dependently enhanced proliferative capacity of H9c2 rat cardiomyoblasts measured by BrdU incorporation assay. Immunhistological analysis of proliferating cardiomyocytes showed an increased number of Ki67+ cardiomyocytes within the infarct border zone 3 days after transplantation of IGF-II overexpressing eEPCs.
Conclusion: Transplantation of IGF-II overexpressing eEPC in acute myocardial infarction may improve myocardial function by enhancing the proliferative capacity of resident cardiomyocyte progenitors.