Mehta Jawahar L, Mercanti Federico, Stone Annjannette, Wang Xianwei, Ding Zufeng, Romeo Francesco, Khaidakov Magomed
*Department of Internal Medicine, Division of Cardiology, Central Arkansas Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR; and †Department of Internal Medicine, Division of Cardiology, University of Rome "Tor Vergata," Rome, Italy.
J Cardiovasc Pharmacol. 2015 Feb;65(2):123-9. doi: 10.1097/FJC.0000000000000118.
Growth of atherosclerotic plaque requires neovascularization (angiogenesis). To elucidate the involvement of angiotensin II (Ang II) in angiogenesis, we performed gene microarray and microRNA (miRNA) polymerase chain reaction array analyses on human coronary artery endothelial cells exposed to moderate concentration of Ang II for 2 and 12 hours. At 12, but not 2, hours, cultures treated with Ang II exhibited shifts in transcriptional activity involving 267 genes (>1.5-fold difference; P < 0.05). Resulting transcriptome was most significantly enriched for genes associated with blood vessel development, angiogenesis, and regulation of proliferation. Majority of upregulated genes implicated in angiogenesis shared a commonality of being either regulators (HES1, IL-18, and CXCR4) or targets (ADM, ANPEP, HES1, KIT, NOTCH4, PGF, and SOX18) of STAT3. In line with these findings, STAT3 inhibition attenuated Ang II-dependent stimulation of tube formation in Matrigel assay. Expression analysis of miRNAs transcripts revealed that the pattern of differential expression for miRNAs was largely consistent with proangiogenic response with a prominent theme of upregulation of miRs targeting PTEN (miR-19b-3p, miR-21-5p, 23b-3p, and 24-3p), many of which are directly or indirectly STAT3 dependent. We conclude that STAT3 signaling may be an intrinsic part of Ang II-mediated proangiogenic response in human endothelial cells.
动脉粥样硬化斑块的生长需要新生血管形成（血管生成）。为了阐明血管紧张素II（Ang II）在血管生成中的作用，我们对暴露于中等浓度Ang II 2小时和12小时的人冠状动脉内皮细胞进行了基因微阵列和微小RNA（miRNA）聚合酶链反应阵列分析。在12小时而非2小时时，用Ang II处理的培养物表现出涉及267个基因的转录活性变化（差异>1.5倍；P<0.05）。所得转录组中与血管发育、血管生成和增殖调控相关的基因富集最为显著。大多数与血管生成相关的上调基因具有共同特点，即它们要么是信号转导和转录激活因子3（STAT3）的调节因子（HES1、IL-18和CXCR4），要么是其靶标（ADM、ANPEP、HES1、KIT、NOTCH4、PGF和SOX18）。与这些发现一致，在基质胶试验中，STAT3抑制减弱了Ang II依赖性的管形成刺激。miRNA转录本的表达分析表明，miRNA的差异表达模式在很大程度上与促血管生成反应一致，其突出特点是靶向磷酸酶和张力蛋白同源物（PTEN）的miR上调（miR-19b-3p、miR-21-5p、23b-3p和24-3p），其中许多直接或间接依赖于STAT3。我们得出结论，STAT3信号传导可能是Ang II介导的人内皮细胞促血管生成反应的内在组成部分。
