C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression
C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression
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DOI：
10.1161/circulationaha.111.041830
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发表时间：
2012-02-28
期刊：
影响因子：
37.8
通讯作者：
Silvestre, Jean-Sebastien
中科院分区：
文献类型：
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作者：
Loinard, Celine;Zouggari, Yasmine;Silvestre, Jean-Sebastien
背景-C/EBP同源蛋白-10（CHOP-10）是一种新的发育调节核蛋白，在调节分化、增殖和存活的途径中作为关键的转录整合子出现。在本研究中，我们分析了CHOP-10在出生后新生血管形成中的作用。方法和结果-缺血是由右股动脉结扎野生型和CHOP-10（-/-）小鼠诱导。在骨骼肌毛细血管结构中，CHOP-10 mRNA和蛋白水平被缺血和糖尿病上调。与野生型小鼠相比，CHOP-10（-/-）小鼠的血管造影评分、毛细血管密度和足部灌注增加。与野生型小鼠相比，这种效应与CHOP-10（-/-）小鼠缺血腿中细胞凋亡减少和内皮型一氧化氮合酶（eNOS）水平上调有关。与这些结果一致，在CHOP-10短干扰RNA转染的人内皮细胞中，eNOS mRNA和蛋白水平显着上调，而CHOP-10的过表达抑制了eNOS启动子的基础转录激活。使用染色质免疫沉淀试验，我们还表明，CHOP-10结合eNOS启动子。有趣的是，CHOP-10（-/-）小鼠中增强的缺血后新血管形成在CHOP-10/eNOS双敲除动物中完全钝化。最后，我们发现，糖尿病的诱导与CHOP-10的显著上调，大大抑制postischemic neovascularization. Conclusions-这项研究确定CHOP-10作为一个重要的转录因子调节血管的形成和成熟。（循环。2012; 125：1014 - 1026）。
Background-C/EBP homologous protein-10 (CHOP-10) is a novel developmentally regulated nuclear protein that emerges as a critical transcriptional integrator among pathways regulating differentiation, proliferation, and survival. In the present study, we analyzed the role of CHOP-10 in postnatal neovascularization.Methods and Results-Ischemia was induced by right femoral artery ligation in wild-type and CHOP-10(-/-) mice. In capillary structure of skeletal muscle, CHOP-10 mRNA and protein levels were upregulated by ischemia and diabetes mellitus. Angiographic score, capillary density, and foot perfusion were increased in CHOP-10(-/-) mice compared with wild-type mice. This effect was associated with a reduction in apoptosis and an upregulation of endothelial nitric oxide synthase (eNOS) levels in ischemic legs of CHOP-10(-/-) mice compared with wild-type mice. In agreement with these results, eNOS mRNA and protein levels were significantly upregulated in CHOP-10 short interfering RNA-transfected human endothelial cells, whereas overexpression of CHOP-10 inhibited basal transcriptional activation of the eNOS promoter. Using a chromatin immunoprecipitation assay, we also showed that CHOP-10 was bound to the eNOS promoter. Interestingly, enhanced postischemic neovascularization in CHOP-10(-/-) mice was fully blunted in CHOP-10/eNOS double-knockout animals. Finally, we showed that induction of diabetes mellitus is associated with a marked upregulation of CHOP-10 that substantially inhibited postischemic neovascularization.Conclusions-This study identifies CHOP-10 as an important transcription factor modulating vessel formation and maturation. (Circulation. 2012;125:1014-1026.)