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Gene Ther. 2014 Apr;21(4):353-62. doi: 10.1038/gt.2014.3. Epub 2014 Feb 6.

A macrophage-specific synthetic promoter for therapeutic application of adiponectin.

Author information

  • 11] Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Korea [2] Center of Molecular Medicine, Graduate School, Chonnam National University, Gwangju, Korea.
  • 21] Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Korea [2] Heart Research Center, Chonnam National University Hospital, Gwangju, Korea.
  • 3Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Korea.
  • 41] Heart Research Center, Chonnam National University Hospital, Gwangju, Korea [2] Department of Cardiology, Chonnam National University Hospital, Gwangju, Korea.
  • 5Department of Cardiology, Chonnam National University Hospital, Gwangju, Korea.
  • 61] Research Laboratory of Cardiovascular Regeneration, Chonnam National University Hospital, Gwangju, Korea [2] Heart Research Center, Chonnam National University Hospital, Gwangju, Korea [3] Department of Cardiology, Chonnam National University Hospital, Gwangju, Korea.

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 p47(phox) 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 p47(phox) promoter element, was successfully developed to target macrophage, and macrophage-specific introduction of APN under SP146-C1 was shown to ameliorate the atherosclerotic pathology.

PMID:
24500526
[PubMed - indexed for MEDLINE]
PMCID:
PMC3975813
Free PMC Article
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