Abstract 9483: High Mobility Group Box 1 Promotes Angiogenesis From Bone Marrow-Derived Endothelial Progenitor Cells After Myocardial Infarction

Abstract

Background: High mobility group box 1 (HMGB1) is a DNA-binding protein secreted into extracellular space from necrotic cells and acts as a cytokine. We have reported that HMGB1 attenuates cardiac damage and restores cardiac function by enhancing angiogenesis after myocardial infarction (MI). We examined the role of HMGB1 in angiogenesis from bone marrow (BM) -derived cells in the heart, using transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-TG). Methods and Results: HMGB1-TG mice and wild-type littermate (WT) mice were lethally irradiated and injected with BM cells from green fluorescent protein (GFP) mice through the tail vein. Two weeks after BM transplantation, the left anterior descending artery was ligated to create MI. In flow cytometry analysis, GFP-positive cells were identified as donor BM cells-derived endothelial progenitor cells (EPC) if they were positive for both CD34 and CD144 in granulocyte differentiation antigen-1-negative fraction. Circulating EPC mobilized from BM was increased at 1 week after MI in HMGB1-TG mice compared with WT mice (41.9% vs. 24.5%, P < 0.01). Histological examination showed the size of MI was smaller in HMGB1-TG mice than in WT mice (42.9% vs. 59.1%, P < 0.01) at 4 weeks after MI. In myocardial immunofluorescence staining, GFP and CD31 double-positive cells were BM-derived cells engrafted within myocardial tissue as vascular endothelial cells of new capillaries or arterioles. The ratio of these double positive cells to all cardiac cells was significantly higher in the HMGB1-TG mice than in the WT mice (8.3% vs. 2.9%, P < 0.01). Enzyme-linked immunosorbent assay revealed that the levels of cardiac vascular endothelial growth factor at 1 week after MI were higher in HMGB1-TG mice than in WT mice (642.1 vs. 390.7 pg/dl, P < 0.05). Conclusions: The present study demonstrated the direct in vivo evidence that HMGB1 promoted angiogenesis and reduced MI size by enhancing mobilization and differentiation of BM cells to EPC, migration to the border zone of MI, and engraftment as vascular endothelial cells of new capillaries or arterioles in the infarcted heart.