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Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice

Gene Therapy volume 11, pages 1772–1779 (2004)Cite this article

Abstract

Inflammation is a major contributor to atherosclerosis by its effects on arterial wall biology and lipoprotein metabolism. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that may modulate the atherosclerotic disease process. We investigated the effects of adeno-associated virus (AAV) vector-mediated gene transfer of IL-10 on atherogenesis in apolipoprotein E (ApoE)-deficient mice. A murine myoblast cell line, C2C12, transduced with AAV encoding murine IL-10 (AAV2-mIL10) secreted substantial amounts of IL-10 into conditioned medium. The production of monocyte chemoattractant protein-1 (MCP-1) by the murine macrophage cell line, J774, was significantly inhibited by conditioned medium from AAV2-mIL10-transduced C2C12 cells. ApoE-deficient mice were injected with AAV5-mIL10 into their anterior tibial muscle at 8 weeks of age. The expression of MCP-1 in the vascular wall of the ascending aorta and serum MCP-1 concentration were decreased in AAV5-mIL10-transduced mice compared with AAV5-LacZ-transduced mice. Oil red-O staining of the ascending aorta revealed that IL-10 gene transfer resulted in a 31% reduction in plaque surface area. Serum cholesterol concentrations were also significantly reduced in AAV5-mIL10-transduced mice. To understand the cholesterol-lowering mechanism of IL-10, we measured the cellular cholesterol level in HepG2 cells, resulting in its significant decrease by the addition of IL-10 in a dose-dependent manner. Furthermore, IL-10 suppressed HMG-CoA reductase expression in the HepG2 cells. These observations suggest that intramuscular injection of AAV5-mIL10 into ApoE-deficient mice inhibits atherogenesis through anti-inflammatory and cholesterol-lowering effects.

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Acknowledgements

We thank Dr John A Chiorini for providing pAAV5-RNL and pAAV5-RepCap (identical to 5RepCapB) and Avigen, Inc. (Alameda, CA, USA) for providing pAAV-LacZ, pHLP19, and pAdeno. We also thank Ms. Miyoko Mitsu for her encouragement and technical support. This study was supported in part by Research Grants from the Ministry of Education, Culture, Sports, Science and Technology; the Ministry of Health, Labor and Welfare; the Vehicle Racing Commemorative Foundation; and Mitsui Social Welfare Foundation.

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Authors and Affiliations

  1. Division of Cardiovascular Medicine, Jichi Medical School, Tochigi, Japan

    T Yoshioka, Y Maeda, M Shimpo, M Nonaka-Sarukawa, T Ito & K Shimada

  2. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

    T Yoshioka, T Okada, T Nomoto, T Matsushita, H Mizukami, Y Hanazono, A Kume & K Ozawa

  3. Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Matsumoto, Japan

    T Yoshioka, U Ikeda & M Takahashi

  4. Department of Anatomy, Jichi Medical School, Tochigi, Japan

    K Takeuchi & S Ookawara

  5. Department of Laboratory Medicine, Jichi Medical School, Tochigi, Japan

    M Kawano

  6. Division of Endocrine and Metabolism, Jichi Medical School, Tochigi, Japan

    S Ishibashi

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  1. T Yoshioka
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Yoshioka, T., Okada, T., Maeda, Y. et al. Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice. Gene Ther 11, 1772–1779 (2004). https://doi.org/10.1038/sj.gt.3302348

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