Transcription Factor Zhx2 Deficiency Reduces Atherosclerosis and Promotes Macrophage Apoptosis in Mice.
Transcription Factor Zhx2 Deficiency Reduces Atherosclerosis and Promotes Macrophage Apoptosis in Mice.
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DOI：
10.1161/atvbaha.118.311266
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发表时间：
2018-09
期刊：
影响因子：
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通讯作者：
Lusis AJ
中科院分区：
文献类型：
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作者：
Erbilgin A;Seldin MM;Wu X;Mehrabian M;Zhou Z;Qi H;Dabirian KS;Sevag Packard RR;Hsieh W;Bensinger SJ;Sinha S;Lusis AJ
探讨近交系BALB/cJ小鼠抗动脉粥样硬化的基础。BALB/cJ小鼠携带编码转录因子Zhx 2的基因的自然发生的无效突变，遗传分析表明，这可能赋予对动脉粥样硬化的抵抗力。在高脂血症Ldlr−/−背景下，与携带野生型等位基因的同基因品系相比，携带Zhx 2突变等位基因的BALB/cJ小鼠的病变大小减少了10倍。包括骨髓（BM）移植研究在内的几条证据表明，Zhx 2的这种作用部分由单核细胞/巨噬细胞介导，尽管非BM来源的途径也明显参与其中。在培养物和动脉粥样硬化病变中，来自Zhx 2缺失小鼠的巨噬细胞表现出显著增加的凋亡。Zhx 2无效巨噬细胞也富集M2标志物。Zhx 2对增殖和其他BM衍生细胞如淋巴细胞的影响最多是适度的。表达微阵列分析鉴定了Zhx 2野生型和无效巨噬细胞之间超过1，000种差异表达的转录物。为了鉴定Zhx 2的全局靶标，我们用巨噬细胞系RAW 264.7进行了ChIP-seq研究。ChIP-seq峰与基因表达非常显著地重叠，并且一起表明了转录抑制和细胞凋亡的作用。在BALB/cJ小鼠中携带的Zhx 2突变在很大程度上是该品系对动脉粥样硬化的相对抗性的原因。我们的研究结果表明，Zhx 2促进巨噬细胞存活和促炎功能在动脉粥样硬化病变，从而有助于病变的生长。
To determine the basis of resistance to atherosclerosis of inbred mouse strain BALB/cJ. BALB/cJ mice carry a naturally occurring null mutation of the gene encoding the transcription factor Zhx2, and genetic analyses suggested that this may confer resistance to atherosclerosis. On a hyperlipidemic Ldlr−/− background BALB/cJ mice carrying the mutant allele for Zhx2 exhibited up to a 10-fold reduction in lesion size as compared to an isogenic strain carrying the wild-type allele. Several lines of evidence, including bone marrow (BM) transplantation studies, indicate that this effect of Zhx2 is mediated in part by monocytes/macrophages, although non-BM-derived pathways are clearly involved as well. Both in culture and in atherosclerotic lesions, macrophages from Zhx2 null mice exhibited substantially increased apoptosis. Zhx2 null macrophages were also enriched for M2 markers. Effects of Zhx2 on proliferation and other BM-derived cells such as lymphocytes were at most modest. Expression microarray analyses identified over 1,000 differentially expressed transcripts between Zhx2 wild-type and null macrophages. To identify the global targets of Zhx2, we performed ChIP-seq studies with the macrophage cell line RAW264.7. The ChIP-seq peaks overlapped very significantly with gene expression and together suggested roles for transcriptional repression and apoptosis. A mutation of Zhx2 carried in BALB/cJ mice is responsible in large part for its relative resistance of the strain to atherosclerosis. Our results indicate that Zhx2 promotes macrophage survival and pro-inflammatory functions in atherosclerotic lesions, thereby contributing to lesion growth.