Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate-Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation.
Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate-Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation.
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DOI：
10.1161/jaha.115.002663
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发表时间：
2016-04-18
影响因子：
5.4
通讯作者：
Paul A
中科院分区：
文献类型：
--
作者：
Goo YH;Son SH;Yechoor VK;Paul A
泡沫细胞是动脉粥样硬化形成中两个主要致病过程的中心：动脉中胆固醇积聚和炎症。动脉中胆固醇沉积的主要潜在原因是高胆固醇血症。本研究旨在评估体内血浆胆固醇升高是否也会改变泡沫细胞的炎症平衡。载脂蛋白E缺陷小鼠在整个研究期间喂食常规小鼠饲料，或在死亡前2周或14周转为西式饮食（WD）。主动脉窦的连续切片用于病变定量或通过激光捕获显微切割（LCM）从泡沫细胞中分离RNA，用于微阵列和定量聚合酶链反应分析。WD喂养2周或14周显著增加了血浆胆固醇，但动脉粥样硬化病变的大小仅在14周WD组中增加。更多的基因表达的影响下，长期高胆固醇血症小鼠的泡沫细胞比在小鼠喂WD 2周。然而，大多数转录编码炎症介质保持不变，在两个WD组。在炎症或免疫反应的主要参与者中，在WD下的小鼠的泡沫细胞中诱导趋化因子（C-X-C基序）配体13 2周。在14周WD组中诱导了干扰素诱导型GTP酶，鸟苷酸结合蛋白（GBP）3和GBP 6，其他GBP家族成员中度增加。我们的研究结果表明，高胆固醇血症加速动脉粥样硬化与泡沫细胞炎症平衡的整体变化无关。然而，GBP的诱导揭示了一个新的免疫调节剂家族，在动脉粥样硬化形成中具有潜在的作用。
Foam cells are central to two major pathogenic processes in atherogenesis: cholesterol buildup in arteries and inflammation. The main underlying cause of cholesterol deposition in arteries is hypercholesterolemia. This study aimed to assess, in vivo, whether elevated plasma cholesterol also alters the inflammatory balance of foam cells. Apolipoprotein E–deficient mice were fed regular mouse chow through the study or were switched to a Western‐type diet (WD) 2 or 14 weeks before death. Consecutive sections of the aortic sinus were used for lesion quantification or to isolate RNA from foam cells by laser‐capture microdissection (LCM) for microarray and quantitative polymerase chain reaction analyses. WD feeding for 2 or 14 weeks significantly increased plasma cholesterol, but the size of atherosclerotic lesions increased only in the 14‐week WD group. Expression of more genes was affected in foam cells of mice under prolonged hypercholesterolemia than in mice fed WD for 2 weeks. However, most transcripts coding for inflammatory mediators remained unchanged in both WD groups. Among the main players in inflammatory or immune responses, chemokine (C‐X‐C motif) ligand 13 was induced in foam cells of mice under WD for 2 weeks. The interferon‐inducible GTPases, guanylate‐binding proteins (GBP)3 and GBP6, were induced in the 14‐week WD group, and other GBP family members were moderately increased. Our results indicate that acceleration of atherosclerosis by hypercholesterolemia is not linked to global changes in the inflammatory balance of foam cells. However, induction of GBPs uncovers a novel family of immune modulators with a potential role in atherogenesis.