SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo.
SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo.
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SNRK（蔗糖非发酵1相关激酶）在体内促进血管生成。
DOI：
10.1161/atvbaha.117.309834
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Zou MH
中科院分区：
文献类型：
--
作者：
Lu Q;Xie Z;Yan C;Ding Y;Ma Z;Wu S;Qiu Y;Cossette SM;Bordas M;Ramchandran R;Zou MH
蔗糖非发酵1（Snf 1）相关激酶（SNRK）是AMP激活蛋白激酶（AMPK）相关超家族的新成员，在血管生成过程中被激活。目前，SNRK在生理和病理条件下的血管生成中的作用尚不清楚。在这项研究中，在Snrk全杂合基因敲除小鼠中，后肢缺血后视网膜血管生成和新血管形成受到抑制。与同窝野生型小鼠相比，EC特异性Snrk缺失的小鼠表现出视网膜血管生成受损，缺血后肢灌注恢复延迟，肌肉凋亡加剧。在非缺血性人的肢体血管样本中，内皮细胞SNRK表达增加。在缺氧条件下培养的内皮细胞中，缺氧诱导因子1α（HIF 1 α）与SNRK启动子结合，上调SNRK表达。在缺氧EC的细胞核中，SNRK与特异性蛋白1（SP1）复合，并且它们一起结合到β1整合素（ITGB 1）启动子中的SP1结合基序，导致ITGB 1表达增强并促进EC迁移。此外，SNRK或SP1缺陷的EC改善缺氧诱导ITGB 1的表达，因此，抑制EC迁移和血管生成。总之，我们的数据显示SNRK/SP1-ITGB 1信号轴促进体内血管生成。
Sucrose non-fermenting 1 (Snf1)-related kinase (SNRK) is a novel member of the AMP-activated protein kinase (AMPK)-related superfamily that is activated in the process of angiogenesis. Currently, little is known about the function of SNRK in angiogenesis in the physiological and pathological condition. In this study, in Snrk global heterozygous knockout mice, retina angiogenesis and neovessel formation after hindlimb ischemia were suppressed. Consistently, mice with EC-specific Snrk deletion exhibited impaired retina angiogenesis, and delayed perfusion recovery and exacerbated muscle apoptosis in ischemic hindlimbs, compared with those of littermate wide-type mice. Endothelial SNRK expression was increased in the extremity vessel samples from non-ischemic human. In endothelial cells (ECs) cultured in hypoxic conditions, hypoxia inducible factor 1α (HIF1α) bound to the SNRK promoter to upregulate SNRK expression. In the nuclei of hypoxic ECs, SNRK complexed with specificity protein 1 (SP1), and together, they bound to an SP1-binding motif in the β1 integrin (ITGB1) promoter, resulting in enhanced ITGB1 expression and promoted EC migration. Furthermore, SNRK or SP1 deficiency in ECs ameliorated hypoxia-induced ITGB1 expression and, consequently, inhibited EC migration and angiogenesis. Taken together, our data have revealed that SNRK/SP1-ITGB1 signaling axis promotes angiogenesis in vivo.