Gene and microRNA transcriptional signatures of angiotensin II in endothelial cells.
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.
*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.
Jawahar L
JL
Mehta
Federico
F
Mercanti
Annjannette
A
Stone
Xianwei
X
Wang
Zufeng
Z
Ding
Francesco
F
Romeo
Magomed
M
Khaidakov
D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000235:genetics; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D000074562:Receptor, Notch4; D019718:Receptors, CXCR4 / Q000235:genetics; D051880:Receptors, Notch / Q000235:genetics; D055760:SOXF Transcription Factors / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
C527276:CXCR4 protein, human; D035683:MicroRNAs; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D019718:Receptors, CXCR4; D051880:Receptors, Notch; D055760:SOXF Transcription Factors; D050796:STAT3 Transcription Factor; D000804:Angiotensin II