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J. Biol. Chem., Vol. 281, Issue 40, 30057-30062, October 6, 2006

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Stat3 Mediates Interelukin-6 Inhibition of Human Endothelial Nitric-oxide Synthase Expression^*

Marta Saura¹, Carlos Zaragoza¹, Clare Bao^¶, Beatriz Herranz, M. Rodriguez-Puyol, and Charles J. Lowenstein^¶2

From the Department of Physiology, Universidad de Alcalá, Alcalá de Henares, 28871 Madrid, Spain, the Fundacion Centro Nacional Investigaciones Cardiovasculares Carlos III (CNIC), Ronda de Poniente, 5, 28760 Tres Cantos, Madrid, Spain, and the ^¶Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Chronic activation of the acute phase response (APR) is associated with atherosclerosis. Elevated levels of interleukin-6, the major inducer of the APR, are associated with an increased risk of cardiovascular events. One of the clinical hallmarks of atherogenesis is endothelial dysfunction, characterized by a decrease in endothelial production of nitric oxide (NO). We hypothesized that interleukin-6 (IL-6) decreases endothelial NO synthase (eNOS) expression. We now show that IL-6 treatment of human aortic endothelial cells (HAEC) decreases steady-state levels of human eNOS mRNA and protein. This decrease in eNOS expression is caused in part by IL-6 inhibition of transactivation of the human eNOS promoter. To explore the mechanism by which IL-6 affects eNOS expression, we examined activation of signal transducer and transactivator-3 (Stat3). The IL-6 receptor (IL-6R) is expressed in HAEC, and Stat3 is phosphorylated in response to IL-6 stimulation of the IL-6R. We identified four consensus sequences for Stat3 binding (SIE) in the eNOS promoter at positions -1520, -1024, -840, and -540. Transfection of eNOS promoter mutants revealed that the SIE at -1024 mediates Stat3 inhibition of eNOS promoter activity. Gel-shift analysis of nuclear extracts from HAEC treated with IL-6 confirms that Stat3 binds to a complex containing the SIE at -1024. RNA silencing of STAT3 blocks the inhibitory effect of IL-6 on eNOS expression. Our data show that IL-6 has direct effects upon endothelial cells, inhibiting eNOS expression in part through Stat3. Decreased levels of eNOS may be an important component of the pro-atherogenic effect of the APR.

Received for publication, June 30, 2006

^* This work was supported in part by National Institutes of Health Grants R01 HL63706, R01 HL074061, P01 HL65608, and P01 HL56091; American Heart Association Grant EIG 0140210N; the Ciccarone Center; the John and Cora H. Davis Foundation (to C. J. L.); and by grants from the Ministerio de Ciencia y Tecnologia (SAF 2002-00399) (to C. Z.) and the Comunidad Autonoma de Madrid (08.4/0023/2003) (to C. Z. and M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both of these authors were supported by the Ramon y Cajal program of the Ministerio de Ciencia y Tecnologia.

² To whom correspondence should be addressed: Dept. of Medicine, The Johns Hopkins University School of Medicine, 950 Ross Bldg., 720 Rutland Ave., Baltimore, MD 21205. E-mail: clowenst{at}jhmi.edu.

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