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

Dayuan Li, Yong Liu, Jiawei Chen, Neelima Velchala, Fariba Amani, Aravind Nemarkommula, Kui Chen, Hassan Rayaz, Dazhi Zhang, Hongmei Liu, Anjan Sinha, Francesco Romeo, Paul L. Hermonat, Jawahar L. Mehta

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)701-707
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume344
Issue number3
DOIs
StatePublished - Jun 9 2006
Externally publishedYes

Fingerprint

Dependovirus
Granulocyte-Macrophage Colony-Stimulating Factor
Viruses
Knockout Mice
Atherosclerosis
Oxidative stress
Genes
Oxidized LDL Receptors
Oxidative Stress
Adhesion
Tissue
Staining and Labeling
Gene therapy
Molecules
LDL Receptors
Nutrition
Oxidants
Genetic Therapy
Transfection
Tail

Keywords

  • Adeno-associated virus
  • Atherosclerosis
  • Granulocyte macrophage-colony stimulating factor
  • Inflammation
  • Oxidation
  • Transforming growth factor β

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

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. / Li, Dayuan; Liu, Yong; Chen, Jiawei; Velchala, Neelima; Amani, Fariba; Nemarkommula, Aravind; Chen, Kui; Rayaz, Hassan; Zhang, Dazhi; Liu, Hongmei; Sinha, Anjan; Romeo, Francesco; Hermonat, Paul L.; Mehta, Jawahar L.

In: Biochemical and Biophysical Research Communications, Vol. 344, No. 3, 09.06.2006, p. 701-707.

Research output: Contribution to journalArticle

Li, D, Liu, Y, Chen, J, Velchala, N, Amani, F, Nemarkommula, A, Chen, K, Rayaz, H, Zhang, D, Liu, H, Sinha, A, Romeo, F, Hermonat, PL & Mehta, JL 2006, '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', Biochemical and Biophysical Research Communications, vol. 344, no. 3, pp. 701-707. https://doi.org/10.1016/j.bbrc.2006.04.010
Li, Dayuan ; Liu, Yong ; Chen, Jiawei ; Velchala, Neelima ; Amani, Fariba ; Nemarkommula, Aravind ; Chen, Kui ; Rayaz, Hassan ; Zhang, Dazhi ; Liu, Hongmei ; Sinha, Anjan ; Romeo, Francesco ; Hermonat, Paul L. ; Mehta, Jawahar L. / 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. In: Biochemical and Biophysical Research Communications. 2006 ; Vol. 344, No. 3. pp. 701-707.
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abstract = "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.",
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T2 - 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

AU - Romeo, Francesco

AU - Hermonat, Paul L.

AU - Mehta, Jawahar L.

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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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