High Mobility Group Box 1 Promotes Angiogenesis from Bone Marrow-derived Endothelial Progenitor Cells after Myocardial Infarction.
OBJECTIVE
High mobility group box 1 (HMGB1) is a DNA-binding protein secreted into the extracellular space from necrotic cells that acts as a cytokine. We examined the role of HMGB1 in angiogenesis from bone marrow-derived cells in the heart using transgenic mice exhibiting the cardiac-specific overexpression of HMGB1 (HMGB1-TG).


METHODS
HMGB1-TG mice and wild-type littermate (WT) mice were lethally irradiated and injected with bone marrow cells from green fluorescent protein mice through the tail vein. After bone marrow transplantation, the left anterior descending artery was ligated to induce myocardial infarction (MI).


RESULTS
Flow cytometry revealed that the levels of circulating endothelial progenitor cells (EPCs) mobilized from the bone marrow increased after MI in the HMGB-TG mice versus the WT mice. In addition, the size of MI was smaller in the HMGB1-TG mice than in the WT mice, and immunofluorescence staining demonstrated that the number of engrafted vascular endothelial cells derived from bone marrow in the border zones of the MI areas was increased in the HMGB1-TG mice compared to that observed in the WT mice. Moreover, the levels of cardiac vascular endothelial growth factor after MI were higher in the HMGB1-TG mice than in the WT mice.


CONCLUSIONS
The present study demonstrated that HMGB1 promotes angiogenesis and reduces the MI size by enhancing the mobilization and differentiation of bone marrow cells to EPCs as well as their migration to the border zones of the MI areas and engraftment as vascular endothelial cells in new capillaries or arterioles in the infarcted heart.
Department of Cardiology and Hematology, Fukushima Medical University.
Yuichi
Y
Nakamura
Satoshi
S
Suzuki
Takeshi
T
Shimizu
Makiko
M
Miyata
Tetsuro
T
Shishido
Kazuhiko
K
Ikeda
Shu-Ichi
S
Saitoh
Isao
I
Kubota
Yasuchika
Y
Takeishi
D000818:Animals; D001853:Bone Marrow / Q000098:blood supply*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000254:growth & development*; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D024243:HMGB1 Protein / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000503:physiopathology*; D018919:Neovascularization, Physiologic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020257:Ventricular Remodeling
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins