TY - JOUR
T1 - Suppression of atherogenesis by delivery of multiscripts(TGF β, 1, mml:none(), mml:none(), ACT) using adeno-associated virus type 2 in LDLR knockout mice
AU - Li, Dayuan
AU - Liu, Yong
AU - Chen, Jiawei
AU - Velchala, Neelima
AU - Amani, Fariba
AU - Nemarkommula, Aravind
AU - Chen, Kui
AU - Rayaz, Hassan
AU - Zhang, Dazhi
AU - Liu, Hongmei
AU - Sinha, Anjan K.
AU - Romeo, Francesco
AU - Hermonat, Paul L.
AU - Mehta, Jawahar L.
PY - 2006/6/9
Y1 - 2006/6/9
N2 - TGFβ1 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 TGFβ1 mutant ( multiscripts(AAV / TGF β, 1, mml:none(), mml:none(), ACT), 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. multiscripts(TGF β, 1, mml:none(), mml:none(), ACT) and GM-CSF (DNA, mRNA, and protein) were highly expressed in the tissues of mice given multiscripts(TGF β, 1, mml:none(), mml:none(), ACT) 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 (nitrotyrosine 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 multiscripts(AAV / TGF β, 1, mml:none(), mml:none(), ACT). Expression of adhesion molecules and LOX-1, oxidative stress, and inflammatory response all were inhibited in the mice given multiscripts(AAV / TGF β, 1, mml:none(), mml:none(), ACT) (P < 0.05 vs. saline-treated or GM-CSF-treated LDLR-/- mice). These data for the first time demonstrate that systemic delivery of multiscripts(TGF β, 1, mml:none(), mml:none(), ACT) gene via AAV can inhibit formation of atherosclerotic lesions, possibly via anti-inflammatory and anti-oxidant mechanisms. These findings suggest a novel view of TGFβ1 in atherogenesis and a potential new gene therapy for treatment of atherosclerosis.
AB - TGFβ1 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 TGFβ1 mutant ( multiscripts(AAV / TGF β, 1, mml:none(), mml:none(), ACT), 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. multiscripts(TGF β, 1, mml:none(), mml:none(), ACT) and GM-CSF (DNA, mRNA, and protein) were highly expressed in the tissues of mice given multiscripts(TGF β, 1, mml:none(), mml:none(), ACT) 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 (nitrotyrosine 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 multiscripts(AAV / TGF β, 1, mml:none(), mml:none(), ACT). Expression of adhesion molecules and LOX-1, oxidative stress, and inflammatory response all were inhibited in the mice given multiscripts(AAV / TGF β, 1, mml:none(), mml:none(), ACT) (P < 0.05 vs. saline-treated or GM-CSF-treated LDLR-/- mice). These data for the first time demonstrate that systemic delivery of multiscripts(TGF β, 1, mml:none(), mml:none(), ACT) gene via AAV can inhibit formation of atherosclerotic lesions, possibly via anti-inflammatory and anti-oxidant mechanisms. These findings suggest a novel view of TGFβ1 in atherogenesis and a potential new gene therapy for treatment of atherosclerosis.
KW - Adeno-associated virus
KW - Atherosclerosis
KW - Granulocyte macrophage-colony stimulating factor
KW - Inflammation
KW - Oxidation
KW - Transforming growth factor β
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UR - http://www.scopus.com/inward/citedby.url?scp=33646138486&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2006.04.010
DO - 10.1016/j.bbrc.2006.04.010
M3 - Article
C2 - 16631603
AN - SCOPUS:33646138486
SN - 0006-291X
VL - 344
SP - 701
EP - 707
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -