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- Title
A macrophage-specific synthetic promoter for therapeutic application of adiponectin.
- Authors
W. S. Kang; J. S. Kwon; H. B. Kim; H-y Jeong; H. J. Kang; M. H. Jeong; J. G. Cho; J. C. Park; Y. S. Kim; Y. Ahn
- Abstract
Foam cell formation from macrophage is a major cause of atherosclerosis. An efficient macrophage-specific promoter is required for the targeting to macrophages. In this study, we develop a macrophage-specific synthetic promoter for the therapeutic application of adiponectin (APN), an antiatherogenic gene. Synthetic promoter-146 (SP146), registered on the NCBI website (http:// www.ncbi.nlm.nih.gov/nuccore/DQ107383), was tested for promoter activities in two non-macrophage cell lines (293 T, HeLa) and a macrophage cell line (RAW264.7, bone marrow-derived macrophages). To enforce macrophage specificity, partial elements of p47phox including the PU.1 site with various lengths (-C1, -C2 and -C3) were inserted next to the synthetic promoters. SP146-C1 showed the highest specificity and efficacy in RAW264.7 cells and was selected for development of an APN-carrying macrophage-specific promoter. Green fluorescent protein (GFP)- or APN-expressing lentivirus under SP146-C1 (Lenti-SP-GFP or Lenti-SP-APN, respectively) showed the highest expression efficacy in RAW264.7 cells compared with the non-macrophage cell lines. APN overexpression in RAW264.7 cells successfully inhibited intracellular lipid accumulation, and atherosclerotic lesions and lipid accumulation were significantly reduced by Lenti-SP-APN in ApoE--/-- atherosclerosis mice. In conclusion, the synthetic promoter SP146-C1, combined with a p47phox promoter element, was successfully developed to target macrophage, and macrophage-specific introduction of APN under SP146-C1 was shown to ameliorate the atherosclerotic pathology.
- Publication
Gene Therapy, 2014, Vol 21, Issue 2, p1
- ISSN
0969-7128
- Publication type
Article
- DOI
10.1038/gt.2014.3