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J. Biol. Chem., Vol. 279, Issue 10, 8792-8801, March 5, 2004

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Hepatocyte Growth Factor Regulates Angiotensin Converting Enzyme Expression^*

Regina M. Day, Gerald Thiel¶, Julie Lum, Rubén D. Chévere, Yongzhen Yang||, Joanne Stevens, Laura Sibert, and Barry L. Fanburg

From the New England Medical Center, Tupper Research Institute, Pulmonary and Critical Care Division, Boston, Massachusetts 02111 and ^¶University of Saarland Medical Center, Department of Medical Biochemistry and Molecular Biology, D-6642 Homburg, Germany

Hepatocyte growth factor (HGF) is a mitogen, morphogen, and motogen that functions in tissue healing and acts as an anti-fibrotic factor. The mechanism for this is not well understood. Recent studies implicate somatic angiotensin-converting enzyme (ACE) in fibrosis. We examined the effects of HGF on ACE expression in bovine pulmonary artery endothelial cells (BPAEC). Short term treatment of BPAEC with HGF transiently increased both ACE mRNA (3 h) and activity (24 h), as determined by ACE protease assays and reverse transcription-PCR. Incubation of BPAEC with HGF for longer periods suppressed ACE mRNA (6 h) and activity (72 h). In contrast, phorbol ester (PMA) treatment produced sustained increase in ACE mRNA and activity. We examined the short term molecular effects of HGF on ACE using PMA for comparison. HGF and PMA increased transcription from a luciferase reporter with the core ACE promoter, which contains a composite binding site for SP1/3 and Egr-1. Immunocytochemistry and electrophoretic mobility shift assay showed that both HGF and PMA increased Egr-1 binding. HGF also increased SP3 binding, as measured by EMSA. However, HGF and PMA increased the cellular activity of only Egr-1, not SP3, as measured by luciferase reporter assays. Deletion of the Egr-1 site in the reporter construct completely abrogated HGF-induced transcription but only 50% of PMA-induced activity. Expression of dominant negative Egr-1 and SP3 blocked up-regulation of the ACE promoter by HGF but only reduced up-regulation by PMA. These results show that HGF transiently increases gene transcription of ACE via activation of Egr-1, whereas PMA regulation involves Egr-1 and additional factor(s).

Received for publication, October 9, 2003 , and in revised form, December 5, 2003.

^* This work was supported by NHLBI, National Institutes of Health Grants R01 HL-14456 and R01 HL-42376. 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.

^|| Current address: University of Texas Medical Branch, Dept. of Pathology, 301 University Blvd., Galveston, TX 77555.

Recipient of an American Lung Association Research Grant and an American Heart Association National Center Scientist Development Grant. To whom correspondence should be addressed. Current address: Dept. of Pharmacology, Georgetown University School of Medicine, 3900 Reservoir Rd., NW, Washington, D. C. 20007. Tel.: 202-687-9709; Fax: 202-687-2585; E-mail: reginamday{at}hotmail.com.

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