Suppression of atherogenesis by delivery of TGFβ1ACT using adeno-associated virus type 2 in LDLR knockout mice

被引:38
作者
Li, Dayuan [1 ]
Liu, Yong [1 ]
Chen, Jiawei [1 ]
Velchala, Neelima [1 ]
Amani, Fariba [1 ]
Nemarkommula, Aravind [1 ]
Chen, Kui [1 ]
Rayaz, Hassan [1 ]
Zhang, Dazhi [1 ]
Liu, Hongmei [1 ]
Sinha, Anjan K. [1 ]
Romeo, Francesco [1 ]
Hermonat, Paul L. [1 ]
Mehta, Jawahar L. [1 ]
机构
[1] Univ Arkansas Med Sci, Gene Therapy Program, Div Cardiovasc Med, VA Med Ctr, Little Rock, AR 72205 USA
关键词
adeno-associated virus; atherosclerosis; granulocyte macrophage-colony stimulating factor; inflammation; oxidation; transforming growth factor beta(1);
D O I
10.1016/j.bbrc.2006.04.010
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
TGF beta(1) deficiency has been attributed to the development of atherosclerosis. There is, however, little direct evidence for this concept. To examine this hypothesis, low-density lipoprotein receptor knockout (LDLR-/-) mice were injected via tail vein with recombinant adeno-associated virus type 2 (rAAV) carrying a bioactive TGF beta(1) mutant (AAV/TGF beta(ACT)(1), n = 10) or granulocyte-macrophage-colony stimulating factor (AAV/GM-CSF, n = 10, a negative control) or saline (n = 9, control), and then put on a high cholesterol diet. At 18 weeks, blood lipids were found to be similarly elevated in all LDLR-/- mice. TGF beta(ACT)(1) and GM-CSF (DNA, mRNA, and protein) were highly expressed in the tissues of mice given TGF beta(ACT)(1) or AAV/GM-CSF, respectively, showing sustained transfection following gene delivery by the systemic route. Saline-treated and AAV/GM-CSF-treated LDLR-/- mice showed extensive areas of atherosclerotic lesion formation. There was evidence of intense oxidative stress (nitrotyrosime staining), inflammation (CD68 staining), and expression of adhesion molecules and the ox-LDL receptor LOX-1 (gene array analysis) in the atherosclerotic tissues. Importantly, atherosclerotic lesion formation was markedly inhibited in the LDLR-/- mice given AAV/TGF beta(ACT)(1). Expression of adhesion molecules and LOX-1, oxidative stress, and inflammatory response all were inhibited in the mice given AAV/TGF beta(ACT)(1) (P < 0.05 vs. saline-treated or GM-CSF-treated LDLR-/- mice). These data for the first time demonstrate that systemic delivery of TGF beta(ACT)(1) gene via AAV can inhibit formation of atherosclerotic lesions, possibly via anti-inflammatory and anti-oxidant mechanisms. These findings suggest a novel view of TGF beta(1) in atherogenesis and a potential new gene therapy for treatment of atherosclerosis. (c) 2006 Elsevier Inc. All rights reserved.
引用
收藏
页码:701 / 707
页数:7
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