Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice
Adeno-associated virus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice
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DOI：
10.1038/sj.gt.3302348
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发表时间：
2004-12-01
期刊：
影响因子：
5.1
通讯作者：
Ozawa, K
中科院分区：
文献类型：
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作者：
Yoshioka, T;Okada, T;Ozawa, K
炎症通过影响动脉壁生物学和脂蛋白代谢而成为动脉粥样硬化的主要原因。白细胞介素-10（IL-10）是一种抗炎细胞因子，可调节动脉粥样硬化疾病的进程。我们研究了腺相关病毒（AAV）载体介导的IL-10基因转移对载脂蛋白E（ApoE）缺陷小鼠动脉粥样硬化形成的影响。用编码鼠IL-10的AAV（AAV 2-mIL 10）转导的鼠成肌细胞系C2 C12向条件培养基中分泌大量的IL-10。由鼠巨噬细胞系J774产生的单核细胞趋化蛋白-1（MCP-1）被来自AAV 2-mIL 10转导的C2 C12细胞的条件培养基显著抑制。在8周龄时将AAV 5-mIL 10注射到ApoE缺陷小鼠的胫前肌中。与AAV 5-LacZ转导的小鼠相比，AAV 5-mIL 10转导的小鼠中升主动脉血管壁中MCP-1的表达和血清MCP-1浓度降低。升主动脉油红O染色显示IL-10基因转移导致斑块表面积减少31%。在AAV 5-mIL 10转导的小鼠中，血清胆固醇浓度也显着降低。为了理解IL-10的降胆固醇机制，我们测量了HepG 2细胞中的细胞胆固醇水平，导致其以剂量依赖性方式通过添加IL-10而显著降低。此外，IL-10抑制HepG 2细胞中HMG-CoA还原酶的表达。这些观察结果表明，将AAV 5-mIL 10肌内注射到ApoE缺陷型小鼠中通过抗炎和降低胆固醇作用抑制动脉粥样硬化形成。
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.