RRC ID 1583
Author Yoshioka T, Okada T, Maeda Y, Ikeda U, Shimpo M, Nomoto T, Takeuchi K, Nonaka-Sarukawa M, Ito T, Takahashi M, Matsushita T, Mizukami H, Hanazono Y, Kume A, Ookawara S, Kawano M, Ishibashi S, Shimada K, Ozawa K.
Title Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice.
Journal Gene Ther.
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.
Volume 11(24)
Pages 1772-9
Published 2004-12
DOI 10.1038/sj.gt.3302348
PII 3302348
PMID 15496963
MeSH Adenoviridae / genetics Animals Aorta / metabolism Apolipoproteins E / deficiency* Arteriosclerosis / immunology Arteriosclerosis / metabolism Arteriosclerosis / pathology Arteriosclerosis / prevention & control* Cell Line Chemokine CCL2 / metabolism Cholesterol / metabolism Gene Transfer Techniques Genetic Therapy / methods* Genetic Vectors / genetics* Hydroxymethylglutaryl CoA Reductases / metabolism Interleukin-10 / biosynthesis Interleukin-10 / genetics* Lipids / blood Male Mice Mice, Inbred C57BL
IF 3.203
Times Cited 51
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL BIOTECHNOLOGY & APPLIED MICROBIOLOGY GENETICS & HEREDITY BIOCHEMISTRY & MOLECULAR BIOLOGY
Resource
DNA material pBluescript SKII+mIL10 (RDB01476)