Opposing roles of STAT-1 and STAT-3 in regulating vascular endothelial growth factor expression in vascular smooth muscle cells
Opposing roles of STAT-1 and STAT-3 in regulating vascular endothelial growth factor expression in vascular smooth muscle cells
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DOI：
10.1016/j.bbrc.2012.10.037
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发表时间：
2012-11-09
影响因子：
3.1
通讯作者：
Wijelath, Errol S.
中科院分区：
文献类型：
--
作者：
Albasanz-Puig, Adaia;Murray, Jacqueline;Wijelath, Errol S.
动脉粥样硬化斑块微血管密度增加在促进斑块不稳定中起主要作用，从而增加中风和心肌梗死的风险。先前我们已经证明，炎症细胞因子Oncostatin-M （OSM）在人类动脉粥样硬化斑块中的表达与微血管密度增加相关，表明OSM在促进斑块血管生成方面的作用。本研究的目的是确定OSM调节人冠状动脉平滑肌细胞血管内皮生长因子（VEGF）表达的机制。通过shRNA和过表达研究，我们发现转录因子STAT-1抑制VEGF表达，而STAT-3促进VEGF表达。我们进一步证明STAT-1和STAT-3调节VEGF表达的机制是通过调节缺氧诱导因子-1 α (HIF-1 α)。STAT-1抑制HIF-1 α的表达，而STAT-3正调控HIF-1 α的表达。这些结果提供了激活STAT-1和STAT-3通过调节HIF-1 α活性间接调节VEGF表达的证据。Elsevier Inc.出版。
Increased microvessel density in atherosclerotic plaques plays a major role in promoting plaque destabilization resulting in increased risk of stroke and myocardial infarction. Previously we have shown that expression of the inflammatory cytokine, Oncostatin-M (OSM), in human atherosclerotic plaques correlated with increased microvessel density, indicating a role for OSM in promoting plaque angiogenesis. The purpose of this study was to determine the mechanism by which OSM regulates Vascular Endothelial Growth Factor (VEGF) expression in human coronary artery smooth muscle cells. Using shRNA and overexpression studies, we have shown that the transcription factor, STAT-1 inhibited VEGF expression, while STAT-3 promoted the expression of VEGF. We further show that the mechanism by which STAT-1 and STAT-3 regulates VEGF expression is through modulation of Hypoxia Inducible Factor-1 alpha (HIF-1 alpha). STAT-1 suppresses HIF-1 alpha expression, whereas STAT-3 positively regulates HIF-1 alpha expression. These results provide evidence that activated STAT-1 and STAT-3 regulate VEGF expression indirectly, by modulating HIF-1 alpha activity. Published by Elsevier Inc.