A macrophage-specific synthetic promoter for therapeutic application of adiponectin

被引：21

作者：

Kang, W. S. ^{[1
,2
]}

Kwon, J. S. ^{[1
,3
]}

Kim, H. B. ^{[1
]}

Jeong, H-y ^{[1
]}

Kang, H. J. ^{[1
]}

Jeong, M. H. ^{[3
,4
]}

Cho, J. G. ^{[4
]}

Park, J. C. ^{[4
]}

Kim, Y. S. ^{[1
,3
]}

Ahn, Y. ^{[1
,3
,4
]}

机构：

[1] Chonnam Natl Univ Hosp, Res Lab Cardiovasc Regenerat, Kwangju 501757, South Korea

[2] Chonnam Natl Univ Hosp, Grad Sch, Ctr Mol Med, Kwangju 501757, South Korea

[3] Chonnam Natl Univ Hosp, Heart Res Ctr, Kwangju 501757, South Korea

[4] Chonnam Natl Univ Hosp, Dept Cardiol, Kwangju 501757, South Korea

来源：

GENE THERAPY | 2014年 / 21卷 / 04期

关键词：

macrophage-specific promoter; foam cell; atherosclerosis; VASCULAR ENDOTHELIAL-CELLS; APOLIPOPROTEIN-A-I; ATHEROSCLEROTIC PLAQUES; REDUCES ATHEROSCLEROSIS; DEFICIENT MICE; GENE-TRANSFER; NITRIC-OXIDE; FOAM CELLS; EXPRESSION; PU.1;

D O I：

10.1038/gt.2014.3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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, He La) 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.

引用

页码：353 / 362

页数：10

共 28 条

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