Activation of the STAT3/microRNA-21 pathway participates in angiotensin II-induced angiogenesis
Activation of the STAT3/microRNA-21 pathway participates in angiotensin II-induced angiogenesis
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STAT3/microRNA-21 通路的激活参与血管紧张素 II 诱导的血管生成
DOI：
10.1002/jcp.28564
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Hu, Hou-Yuan
中科院分区：
文献类型：
--
作者：
Chen, Li-Yuan;Wang, Xue;Hu, Hou-Yuan
血管紧张素II（AngII）促进血管生成，这与动脉粥样硬化斑块的持续进展有关，但其潜在机制仍不完全清楚。一些microRNA（miRNAs）已被证明可以促进血管生成;然而，miRNAs是否在AngII诱导的血管生成中起关键作用仍不清楚。本研究评估了miRNA-21（miR-21）在人微血管内皮细胞（HMEC）中AngII介导的促血管生成反应中的功能参与。我们发现，血管紧张素II发挥了促血管生成的作用，促进HMEC的增殖，迁移和管的形成。接下来，发现miR-21在AngII处理的HMEC中上调，并且其特异性抑制剂有效地阻断AngII的促血管生成作用。随后，我们集中在血管紧张素II介导的促血管生成过程中的STAT 3的组成性激活。生物信息学分析表明STAT 3是启动miR-21表达的转录因子，ChIP-PCR验证了这一点。报告基因测定进一步鉴定了miR-21启动子区中STAT 3的三个功能性结合位点。此外，磷酸酶和张力蛋白同源物（PTEN）被认为是miR-21的靶点，STAT 3抑制恢复了AngII诱导的PTEN减少。同样，STAT 3/miR-21轴被证明可以介导AngII引起的体内血管生成，这一点通过使用适当的抑制剂得到了证明。我们的数据表明，AngII通过上调miR-21和降低PTEN表达参与促血管生成反应，这至少部分与STAT 3信号传导有关。本研究为AngII诱导的血管生成提供了新的见解，并提出了减缓动脉粥样硬化病变进展和预防动脉粥样硬化并发症的潜在治疗策略。
Angiotensin II (AngII) facilitates angiogenesis that is associated with the continuous progression of atherosclerotic plaques, but the underlying mechanisms are still not fully understood. Several microRNAs (miRNAs) have been shown to promote angiogenesis; however, whether miRNAs play a crucial role in AngII-induced angiogenesis remains unclear. This study evaluated the functional involvement of miRNA-21 (miR-21) in the AngII-mediated proangiogenic response in human microvascular endothelial cells (HMECs). We found that AngII exerted a proangiogenic role, indicated by the promotion of proliferation, migration, and tube formation in HMECs. Next, miR-21 was found to be upregulated in AngII-treated HMECs, and its specific inhibitor potently blocked the proangiogenic effects of AngII. Subsequently, we focused on the constitutive activation of STAT3 in the AngII-mediated proangiogenic process. Bioinformatic analysis indicated that STAT3 acted as a transcription factor initiating miR-21 expression, which was verified by ChIP-PCR. A reporter assay further identified three functional binding sites of STAT3 in the miR-21 promoter region. Moreover, phosphatase and tensin homolog (PTEN) was recognized as a target of miR-21, and STAT3 inhibition restored AngII-induced reduction in PTEN. Similarly, the STAT3/miR-21 axis was shown to mediate AngII-provoked angiogenesis in vivo, which was demonstrated by using the appropriate inhibitors. Our data suggest that AngII was involved in proangiogenic responses through miR-21 upregulation and reduced PTEN expression, which was, at least in part, linked to STAT3 signaling. The present study provides novel insights into AngII-induced angiogenesis and suggests potential treatment strategies for attenuating the progression of atherosclerotic lesions and preventing atherosclerosis complications.