HIF1α-induced upregulation of KLF4 promotes migration of human vascular smooth muscle cells under hypoxia
HIF1α-induced upregulation of KLF4 promotes migration of human vascular smooth muscle cells under hypoxia
复制标题
HIF1α诱导KLF4上调促进缺氧下人血管平滑肌细胞迁移
DOI：
10.1002/jcp.28953
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Li, Junxia
中科院分区：
文献类型：
--
作者：
Shan, Fabo;Huang, Zhizhong;Li, Junxia
缺氧诱导的血管平滑肌细胞（VSMCs）迁移在血管重塑中起重要作用，并与动脉粥样硬化和肺动脉高压等血管疾病有关。我们先前观察到在缺氧条件下，VSMCs中Kruppel样因子4（KLF 4）的表达增加。然而，KLF 4的上调是否参与了缺氧诱导的VSMCs迁移尚不清楚。在这项研究中，我们证明了KLF 4是一个重要的球员在缺氧条件下的VSMCs迁移的过程中，因为KLF 4的干扰小干扰RNA主要抑制缺氧诱导的VSMCs的迁移。此外，我们使用荧光素酶报告基因和ChIP检测，证实了两个低氧诱导因子1 α（HIF 1 α）的结合元件（位于-150至-163和-3922至-3932）的上游调控区的klf 4基因座，并确定KLF 4作为一个新的直接靶基因HIF 1 α。我们的研究结果揭示了一种新的调节机制，涉及HIF 1 α诱导的KLF 4上调，这在缺氧条件下VSMC迁移中起着至关重要的作用。
Hypoxia-induced vascular smooth muscle cells (VSMCs) migration plays an important role in vascular remodeling and is implicated in vascular diseases, such as atherosclerosis and pulmonary hypertension. We previously observed the increased expression of kruppel-like factor 4 (KLF4) in VSMCs under hypoxia. However, whether the upregulation of KLF4 participates in hypoxia-induced VSMCs migration is still unknown. In this study, we demonstrated that KLF4 was an important player in the process of VSMCs migration under hypoxia since interference of KLF4 by small interfering RNA mostly dampened hypoxia-induced migration of VSMCs. In addition, using luciferase reporter and ChIP assays, we confirmed two hypoxia-inducible factor 1 alpha (HIF1 alpha) binding elements (located at -150 to -163 and -3922 to -3932) in the upstream regulatory region of klf4 locus and identified KLF4 as a novel direct target gene of HIF1 alpha. Our findings unveil a novel regulatory mechanism that involves HIF1 alpha-induced upregulation of KLF4, which plays a vital role in VSMCs migration under hypoxia.