Systemic application of 3-methyladenine markedly inhibited atherosclerotic lesion in ApoE(-/-) mice by modulating autophagy, foam cell formation and immune-negative molecules.
Systemic application of 3-methyladenine markedly inhibited atherosclerotic lesion in ApoE(-/-) mice by modulating autophagy, foam cell formation and immune-negative molecules.
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全身应用 3-甲基腺嘌呤通过调节自噬、泡沫细胞形成和免疫阴性分子，显着抑制 ApoE-/- 小鼠的动脉粥样硬化病变。
DOI：
10.1038/cddis.2016.376
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发表时间：
2016-12-01
影响因子：
9
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Dai S;Wang B;Li W;Wang L;Song X;Guo C;Li Y;Liu F;Zhu F;Wang Q;Wang X;Shi Y;Wang J;Zhao W;Zhang L
越来越多的证据表明，自噬作为一种进化上保守的细胞内降解过程，参与了动脉粥样硬化的发病机制，并已成为一个潜在的治疗靶点。在这里，我们测试了两种磷脂酰肌醇3-激酶抑制剂，3-甲基腺嘌呤（3-MA）和2-（4-吗啉基）-8-苯基色酮（LY 294002），通常用作自噬抑制剂，在载脂蛋白E−/−小鼠动脉粥样硬化中的作用。与对照组相比，全身应用3-MA而不是LY 294002显著降低了高脂饮食喂养小鼠的动脉粥样硬化斑块的大小，并增加了病变的稳定性。此外，3-MA具有多种动脉粥样硬化保护作用，包括调节巨噬细胞自噬和泡沫细胞形成以及改变免疫微环境。长期治疗3-MA促进氧化低密度脂蛋白（oxLDL）诱导的巨噬细胞自噬和抑制泡沫细胞的形成和细胞活力在体外。此外，全身应用3-MA可促进脂滴分解并减少细胞凋亡，这很可能与自噬相关。3-MA处理显著增强免疫阴性分子如白细胞介素10（IL-10）、转化生长因子β和IL-35以及调节性T细胞的特异性转录因子叉头盒P3（Foxp 3）的表达，但不影响动脉壁中促炎细胞因子的水平。我们为3-MA在抑制动脉粥样硬化发展和改善斑块稳定性方面的潜在治疗益处提供了强有力的证据。
A growing body of evidence demonstrates that autophagy, an evolutionarily conserved intracellular degradation process, is involved in the pathogenesis of atherosclerosis and has become a potential therapeutic target. Here we tested the effect of two inhibitors of phosphatidylinositol 3-kinase, 3-methyladenine (3-MA) and 2-(4-morpholinyl)-8-phenyl-chromone (LY294002), commonly used as inhibitors of autophagy, in atherosclerosis in apolipoprotein E−/− mice. Systemic application of 3-MA but not LY294002 markedly reduced the size of atherosclerotic plaque and increased the stability of lesions in high-fat diet-fed mice as compared with controls. Furthermore, 3-MA had multiple atheroprotective effects, including modulating macrophage autophagy and foam cell formation and altering the immune microenvironment. Long-term treatment with 3-MA promoted oxidized low-density lipoprotein (oxLDL)-induced macrophage autophagy and suppressed foam cell formation and cell viability in vitro. Furthermore, systemic application of 3-MA promoted lipid droplet breakdown and decreased apoptosis, most likely associated with autophagy. 3-MA treatment strikingly enhanced the expression of immune-negative molecules such as interleukin 10 (IL-10), transforming growth factor β and IL-35, as well as forkhead box P3 (Foxp3), the specific transcriptional factor for regulatory T cells, but did not affect the level of proinflammatory cytokines in the arterial wall. We provide strong evidence for the potential therapeutic benefit of 3-MA in inhibiting atherosclerosis development and improving plaque stability.