Systemic human Netrin-1 gene delivery by adeno-associated virus type 8 alters leukocyte accumulation and atherogenesis in vivo

被引：38
作者：
Khan, J. A. [1 ,2 ]
Cao, M. [1 ,2 ]
Kang, B. Y. [1 ,2 ,3 ,4 ]
Liu, Y. [1 ,2 ]
Mehta, J. L. [1 ,2 ]
Hermonat, P. L. [1 ,2 ]
机构：
[1] Univ Arkansas Med Sci, Div Cardiol, Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA
[2] VA Med Ctr, Little Rock, AR USA
[3] Atlanta Vet Affairs Med Ctr, Dept Med, Atlanta, GA USA
[4] Emory Univ Med Ctr, Dept Med, Atlanta, GA USA
来源：
GENE THERAPY | 2011年 / 18卷 / 05期
关键词：
atherosclerosis; macrophage; suppressor T cell; chemo-repellent; adeno-associated virus; REGULATORY T-CELLS; ATHEROSCLEROSIS; MIGRATION; OVEREXPRESSION; TRANSDUCTION; INFLAMMATION; EXPRESSION; DISEASE; VECTOR; LOX-1;
D O I：
10.1038/gt.2010.155
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：
Atherosclerosis is an inflammatory disorder of arteries. Atherosclerotic plaque, in its early to intermediate stages, is composed largely of lipid-engorged foam cells. These foam cells are derived from the trafficking of monocytes (Mo) into the arterial intima, attracted to the site by chemoattractants. Given that foam cells are derived from the trafficking of Mo, the use of Netrin-1, an Mo chemorepellent, may be useful in limiting Mo accumulation and subsequent plaque formation. To investigate the potential of Netrin-1 for limiting atherosclerosis, we systemically delivered its human (h) cDNA by adeno-associated virus type 8 (AAV8, single-stranded structure) delivery into low-density lipoprotein receptor knockout (LDLR-/-) mice and placed the animals on a high cholesterol diet (HCD). Compared with control neomycin resistance (Neo) gene delivery/HCD, hNetrin-1 delivery resulted in a significant reduction in plaque formation, as determined by larger aortic lumen size, thinner intima media thickness and lower blood velocity than the Neo/HCD control (all statistically significant). Indices of monocyte/macrophage (Mo/M Phi) accumulation, CD68, integrin, alpha M (ITGAM) and egf-like module containing, mucin-like, hormone receptor-like 1 (EMR-1), were reduced in hNetrin-1/HCD-treated animal's aortas and spleens compared with Neo/HCD-treated animals. Unexpectedly, CD25 and foxp3 (regulatory T cells (Tregs)) in the aorta were strongly upregulated. This is the first time the Mo/M Phi chemorepellent approach, and specific Netrin-1 gene delivery, has been performed for the reduction of Mo/M Phi burden and atherosclerosis. In addition, Netrin-1 has never before been linked to altered Treg levels. These data strongly suggest that hNetrin-1 gene delivery can reduce Mo/M Phi accumulation, inflammation and subsequent plaque formation. Gene Therapy (2011) 18, 437-444; doi:10.1038/gt.2010.155; published online 16 December 2010
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收藏
页码：437 / 444
页数：8
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