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

来源：

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS | 2006年 / 344卷 / 03期

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

页码：701 / 707

页数：7