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J. Biol. Chem., Vol. 283, Issue 29, 20027-20036, July 18, 2008

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Characterization of the Human ₁β₁ Soluble Guanylyl Cyclase Promoter

KEY ROLE FOR NF-B(p50) AND CCAAT-BINDING FACTORS IN REGULATING EXPRESSION OF THE NITRIC OXIDE RECEPTOR^*

Martín L. Marro, Concepción Peiró¹, Catherine M. Panayiotou, Reshma S. Baliga, Sabine Meurer^¶, Harald H. H. W. Schmidt^¶, and Adrian J. Hobbs²

From the Department of Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, United Kingdom, the Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain, and the ^¶Department of Pharmacology, Monash University, Faculty of Medicine, Melbourne, Victoria 3168, Australia

Soluble guanylyl cyclase (sGC) is the principal receptor for NO and plays a ubiquitous role in regulating cellular function. This is exemplified in the cardiovascular system where sGC governs smooth muscle tone and growth, vascular permeability, leukocyte flux, and platelet aggregation. As a consequence, aberrant NO-sGC signaling has been linked to diseases including hypertension, atherosclerosis, and stroke. Despite these key (patho)physiological roles, little is known about the expressional regulation of sGC. To address this deficit, we have characterized the promoter activity of human ₁ and β₁ sGC genes in a cell type relevant to cardiovascular (patho)physiology, primary human aortic smooth muscle cells. Luciferase reporter constructs revealed that the 0.3- and 0.5-kb regions upstream of the transcription start sites were optimal for ₁ and β₁ sGC promoter activity, respectively. Deletion of consensus sites for c-Myb, GAGA, NFAT, NF-B(p50), and CCAAT-binding factor(s) (CCAAT-BF) revealed that these are the principal transcription factors regulating basal sGC expression. In addition, under pro-inflammatory conditions, the effects of the strongest ₁ and β₁ sGC repressors were enhanced, and enzyme expression and activity were reduced; in particular, NF-B(p50) is pivotal in regulating enzyme expression under such conditions. NO itself also elicited a cGMP-independent negative feedback effect on sGC promoter activity that is mediated, in part, via CCAAT-BF activity. In sum, these data provide a systematic characterization of the promoter activity of human sGC ₁ and β₁ subunits and identify key transcription factors that govern subunit expression under basal and pro-inflammatory (i.e. atherogenic) conditions and in the presence of ligand NO.

Received for publication, February 14, 2008 , and in revised form, May 9, 2008.

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^* This work was supported by the Wellcome Trust. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.

¹ Supported by Comunidad Autónoma de Madrid Grant CCG07-UAM/BIO-1595.

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² Recipient of a Wellcome Trust Senior Research Fellowship. To whom correspondence should be addressed: Dept. of Pharmacology, University Collage London, Medical Sciences Bldg., Gower St., London WC1E 6BT, UK. Tel.: 44-20-7679-7161; Fax: 44-20-7679-7298; E-mail: a.hobbs{at}ucl.ac.uk.

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