Published online before print September 13, 2007, doi: 10.1161/CIRCRESAHA.107.152439
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Submitted on March 23, 2007
Revised on August 27, 2007
Accepted on September 5, 2007
Ets-1 Is a Critical Transcriptional Regulator of Reactive Oxygen Species and p47phox Gene Expression in Response to Angiotensin II
Weihua Ni ;
From the Division of Cardiology (W.N., Y.Z., E.M., P.O.), Beth Israel Deaconess Medical Center; and NMR Laboratory for Physiological Chemistry (H.H., J.A.B.), Brigham and Women's Hospital, Boston, Mass. Present address for H.H.: Department of Anesthesiology, Children's Hospital, Harvard Medical School, Boston, Mass.
* To whom correspondence should be addressed. E-mail: joettgen{at}bidmc.harvard.edu.
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 p47phox 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 p47phox.
Key words: ETS factor • Ets-1 • vascular inflammation • transcription factor
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