Cellular Repressor of E1A-Stimulated Genes Is a Critical Determinant of Vascular Remodeling in Response to Angiotensin II
Cellular Repressor of E1A-Stimulated Genes Is a Critical Determinant of Vascular Remodeling in Response to Angiotensin II
复制标题
E1A 刺激基因的细胞阻遏物是血管紧张素 II 引起的血管重塑的关键决定因素
DOI：
10.1161/atvbaha.116.308794
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发表时间：
2017-03-01
影响因子：
8.7
通讯作者：
Han, Yaling
中科院分区：
文献类型：
--
作者：
Li, Yang;Liu, Yanxia;Han, Yaling
目的：E1a刺激基因的细胞抑制因子(CREG)是一种溶酶体糖蛋白，参与维持血管内环境的稳定。方法和结果：在高盐诱导的Dahl盐敏感大鼠和Ang II诱导的小鼠血管重塑组织中，CREG基因表达显著降低，同时血管紧张素II(Ang II)表达上调。尤其是CREG基因的下调是Ang II特异性的，且不受血压的影响。注射Ang II的CREG(+/-)小鼠的胸主动脉和肠系膜动脉的中膜肥厚和血管纤维化明显高于CREG(+/+)小鼠，但CREG(+/+)小鼠接受重组人CREG蛋白后反应迟钝，提示CREG表达的变化是不同基因型别表型差异的原因。在平铺启动子阵列中，在Ang II的刺激下，E26转化特异性1与CREG启动子高度结合。而且，Ang II诱导的E26转化特异性1直接与CREG启动子(-1179和-271bp)相互作用，并抑制其在血管平滑肌细胞中的转录。选择性、药理抑制E26转化特异性1可恢复CREG在主动脉中的表达，并通过全身应用显性负性E26转化特异性1膜通透性多肽来挽救实验性血管重塑。结论CREG是血管紧张素转换酶II诱导的血管重塑的一种新的介导物，可能成为预防血管疾病的有效治疗靶点。
Objective-Cellular repressor of E1A-stimulated genes (CREG) is a lysosomal glycoprotein implicated in maintaining vascular homeostasis. Here, we have hypothesized that CREG is a critical target of intervention for the prevention of hypertensive vascular remodeling.Approach and Results-CREG gene expression was significantly decreased accompanied by an upregulated expression of angiotensin II (Ang II) in remodeled vascular tissues of high salt-induced Dahl salt-sensitive rats and Ang II-induced mice. In particular, the downregulation of CREG gene was Ang II specific and independent from blood pressure. Prominent medial hypertrophy and vascular fibrosis in both thoracic aortas and mesenteric arteries were observed in CREG(+/-) mice infused with Ang II than in CREG(+/+) mice, but blunted response in CREG(+/+) mice received recombinant human CREG protein, suggesting that changes in CREG expression account for the different phenotype between genotypes. Within a tiled promoter array, E26 transformation-specific-1 binds to CREG promoter at high stringency with the stimulation of Ang II. Moreover, the Ang II-induced E26 transformation-specific-1 directly interacted with the CREG promoter (-1179 and -271 bp) and inhibited its transcription in vascular smooth muscle cells. Selective, pharmacological inhibition of E26 transformation-specific-1 led to restoration of CREG expression in aortas and rescue of experimental vascular remodeling by systemic administration of dominant negative E26 transformation-specific-1 membrane-permeable peptides.Conclusions-CREG is a novel mediator of vascular remodeling in response to Ang II and may be an attractive therapeutic target for prevention of vascular diseases.