Suppression of atherogenesis by delivery of TGFbeta1ACT using adeno-associated virus type 2 in LDLR knockout mice.
TGFbeta(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 TGFbeta(1) mutant (AAV/TGFbeta1ACT, 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. TGFbeta1ACT and GM-CSF (DNA, mRNA, and protein) were highly expressed in the tissues of mice given TGFbeta1ACT 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 AAV/TGFbeta1ACT. Expression of adhesion molecules and LOX-1, oxidative stress, and inflammatory response all were inhibited in the mice given AAV/TGFbeta1ACT (P<0.05 vs. saline-treated or GM-CSF-treated LDLR(-/-) mice). These data for the first time demonstrate that systemic delivery of TGFbeta1ACT gene via AAV can inhibit formation of atherosclerotic lesions, possibly via anti-inflammatory and anti-oxidant mechanisms. These findings suggest a novel view of TGFbeta(1) in atherogenesis and a potential new gene therapy for treatment of atherosclerosis.
Li
Dayuan
D
Gene Therapy Program, Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, VA Medical Center, Little Rock, AR 72205, USA.
Liu
Yong
Y
Chen
Jiawei
J
Velchala
Neelima
N
Amani
Fariba
F
Nemarkommula
Aravind
A
Chen
Kui
K
Rayaz
Hassan
H
Zhang
Dazhi
D
Liu
Hongmei
H
Sinha
Anjan K
AK
Romeo
Francesco
F
Hermonat
Paul L
PL
Mehta
Jawahar L
JL
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D014162:Transfection / Q000379:methods; D016212:Transforming Growth Factor beta / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D016896:Treatment Outcome
D011973:Receptors, LDL; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1