...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Endocrinology >Inhibiting DNA Methylation by 5-Aza-2 '-deoxycytidine Ameliorates Atherosclerosis Through Suppressing Macrophage Inflammation
【24h】

Inhibiting DNA Methylation by 5-Aza-2 '-deoxycytidine Ameliorates Atherosclerosis Through Suppressing Macrophage Inflammation

机译：5-Aza-2'-脱氧胞苷抑制DNA甲基化通过抑制巨噬细胞炎症改善动脉粥样硬化。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Inflammation marks all stages of atherogenesis. DNA hypermethylation in the whole genome or specific genes is associated with inflammation and cardiovascular diseases. Therefore, we aimed to study whether inhibiting DNA methylation by DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) ameliorates atherosclerosis in low-density lipoprotein receptor knockout (Ldlr(-/-)) mice. Ldlr(-/-) mice were fed an atherogenic diet and adminisered saline or 5-aza-dC (0.25 mg/kg) for up to 30 weeks. 5-aza-dC treatment markedly decreased atherosclerosis development in Ldlr(-/-) mice without changes in body weight, plasma lipid profile, macrophage cholesterol levels and plaque lipid content. Instead, this effect was associated with decreased macrophage inflammation. Macrophages with 5-aza-dC treatment had downregulated expression of genes involved in inflammation (TNF-alpha, IL-6, IL-1 beta, and inducible nitric oxidase) and chemotaxis (CD62/L-selectin, chemokine [C-C motif] ligand 2/MCP-1 [CCL2/MCP-1], CCL5, CCL9, and CCL2 receptor CCR2). This resulted in attenuated macrophage migration and adhesion to endothelial cells and reduced macrophage infiltration into atherosclerotic plaques. 5-aza-dC also suppressed macrophage endoplasmic reticulum stress, a key upstream signal that activates macrophage inflammation and apoptotic pathways. Finally, 5-aza-dC demethylated liver X receptor alpha (LXR alpha) and peroxisome proliferator-activated receptor gamma 1 (PPAR gamma 1) promoters, which are both enriched with CpG sites. This led to overexpression of LXR alpha and PPAR gamma, which may be responsible for 5-aza-dC's anti-inflammatory and atheroprotective effect. Our findings provide strong evidence that DNA methylation may play a significant role in cardiovascular diseases and serve as a therapeutic target for prevention and treatment of atherosclerosis.
机译：炎症标志着动脉粥样硬化的各个阶段。整个基因组或特定基因中的DNA超甲基化与炎症和心血管疾病有关。因此，我们旨在研究通过DNA甲基转移酶抑制剂5-氮杂2'-脱氧胞苷（5-氮杂-dC）抑制DNA甲基化是否能改善低密度脂蛋白受体敲除（Ldlr（-/-））小鼠的动脉粥样硬化。向Ldlr（-/-）小鼠喂食致动脉粥样化饮食，并给予生理盐水或5-氮杂-dC（0.25 mg / kg），长达30周。 5-氮杂-dC处理显着降低Ldlr（-/-）小鼠的动脉粥样硬化发展，而体重，血浆脂质谱，巨噬细胞胆固醇水平和斑块脂质含量均无变化。相反，这种作用与减少的巨噬细胞炎症有关。接受5-氮杂-dC处理的巨噬细胞下调了与炎症相关的基因（TNF-α，IL-6，IL-1β和诱导型一氧化氮酶）和趋化性（CD62 / L-选择素，趋化因子[CC]配体）的表达2 / MCP-1 [CCL2 / MCP-1]，CCL5，CCL9和CCL2受体CCR2）。这导致减弱的巨噬细胞迁移和粘附于内皮细胞，并减少巨噬细胞向动脉粥样硬化斑块的浸润。 5-氮杂-dC还抑制巨噬细胞内质网应激，这是激活巨噬细胞炎症和凋亡途径的关键上游信号。最后，5-氮杂-dC脱甲基肝X受体α（LXRα）和过氧化物酶体增殖物激活的受体γ1（PPARγ1）启动子，都富含CpG位点。这导致LXRα和PPARγ的过表达，这可能是5-氮杂-dC的抗炎和抗动脉粥样硬化作用的原因。我们的发现提供了有力的证据，证明DNA甲基化可能在心血管疾病中发挥重要作用，并成为预防和治疗动脉粥样硬化的治疗靶标。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号