Ets-1 is a critical transcriptional regulator of reactive oxygen species and p47(phox) gene expression in response to angiotensin II.
Angiotensin (Ang) II is a potent mediator of vascular inflammation. A central mechanism by which Ang II promotes inflammation is through the generation of reactive oxygen species (ROS). In the current study, we investigated the role of the transcription factor Ets-1 in regulating Ang II-induced ROS generation. ROS generation was measured in the thoracic aorta of Ets-1(-/-) mice compared with littermate controls after continuous infusion of Ang II. H2O2 and superoxide anion (O2(-)) production were significantly blunted in the Ets-1(-/-) mice. Inhibition of Ets-1 expression by small interfering RNA in primary human aortic smooth muscle cells also potently inhibited ROS production and the induction of the NAD(P)H oxidase subunit p47(phox) in response to Ang II. To evaluate the therapeutic potential of inhibiting Ets-1 in wild-type mice, dominant negative Ets-1 membrane-permeable peptides were administered systemically. Ang II-induced ROS production and medial hypertrophy in the thoracic aorta were markedly diminished as a result of blocking Ets-1. In summary, Ets-1 functions as a critical downstream transcriptional mediator of Ang II ROS generation by regulating the expression of NAD(P)H oxidase subunits such as p47(phox).
Ni
Weihua
W
Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Zhan
Yumei
Y
He
Huamei
H
Maynard
Elizabeth
E
Balschi
James A
JA
Oettgen
Peter
P
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D016297:Mutagenesis, Site-Directed; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology
C494041:ETS1 protein, human; C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D017382:Reactive Oxygen Species; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1