IADR Abstract Archives
miR126 Vascular Therapeutics: Friend or Foe?
Objectives: Recent studies have identified miR-126 as an essential mediator of vascular integrity and angiogenesis by regulating the responses of endothelial cells to vascular endothelial growth factor (VEGF). Furthermore, in atherosclerosis related pathology, it has been shown to reduce the macrophage and apoptotic cell content of plaques through increased CXCL12 expression, which has also been show to promote endothelial progenitor cell migration to repair the vasculature. miR126 therefore represents a unique therapeutic potential in vascular biology and atherosclerosis. This project will test the hypothesis that genetically manipulated macrophage expression of miR126 will facilitate vascular protection
Methods: Lenti-SMP-miR126 vector was constructed using primary miR126 DNA and cold fusion cloning. apoE-/-mice were transplanted with HSC-enriched bone marrow cells transduced with control or miR126 driven by a synthetic macrophage promoter. After 4 weeks recovery, the mice were fed a high fat diet for 8weeks, and then sacrificed. Reduction of atherosclerotic plaque size was determined by Oil red-O and H&E staining of 10µm aortic root sections. Flow cytometry analysis of circulating Sca1+ Lin- progenitor cells and immunofluorescence staining of aortic root sections to determine CXCL12 expression was used to verify the activation of the CXCR4/CXCL12 axis
Results: miR126 over-expression in vivo displays a therapeutic reduction in atherosclerosis plaque size without any significant changes in plaque stability. There was an increase in both the expression of CXCL12 in aortic root sections and the number of circulating Sca1+Lin- progenitors. These changes may be attributed to miR126 regulation of progenitor cell mobilization through activation of the CXCR4/CXCL12 axis
Conclusions: Over-expression of miR126 in macrophages represents a novel therapeutic in vascular biology
Methods: Lenti-SMP-miR126 vector was constructed using primary miR126 DNA and cold fusion cloning. apoE-/-mice were transplanted with HSC-enriched bone marrow cells transduced with control or miR126 driven by a synthetic macrophage promoter. After 4 weeks recovery, the mice were fed a high fat diet for 8weeks, and then sacrificed. Reduction of atherosclerotic plaque size was determined by Oil red-O and H&E staining of 10µm aortic root sections. Flow cytometry analysis of circulating Sca1+ Lin- progenitor cells and immunofluorescence staining of aortic root sections to determine CXCL12 expression was used to verify the activation of the CXCR4/CXCL12 axis
Results: miR126 over-expression in vivo displays a therapeutic reduction in atherosclerosis plaque size without any significant changes in plaque stability. There was an increase in both the expression of CXCL12 in aortic root sections and the number of circulating Sca1+Lin- progenitors. These changes may be attributed to miR126 regulation of progenitor cell mobilization through activation of the CXCR4/CXCL12 axis
Conclusions: Over-expression of miR126 in macrophages represents a novel therapeutic in vascular biology