HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 10, 9287-9297, March 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/10/9287    most recent M309227200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anderson, H. D. I. Articles by Gardner, D. G. Search for Related Content PubMed PubMed Citation Articles by Anderson, H. D. I. Articles by Gardner, D. G. Social Bookmarking                      What's this?

Role of the Epidermal Growth Factor Receptor in Signaling Strain-dependent Activation of the Brain Natriuretic Peptide Gene^*

Hope D. I. Anderson, Feng Wang, and David G. Gardner¶

From the Diabetes Center and Department of Medicine, University of California, San Francisco, California 94143-0540

The epidermal growth factor receptor (EGFR) and ectoshedding of heparin-binding epidermal growth factor (HBEGF), an EGFR ligand, have been linked to the development of cardiac myocyte hypertrophy. However, the precise role that the liganded EGFR plays in the transcriptional activation of the gene program that accompanies hypertrophy remains undefined. Utilizing the human (h) BNP gene as a model of hypertrophy-dependent gene activation, we show that activation of the EGFR plays an important role in mediating mechanical strain-dependent stimulation of the hBNP promoter. Strain promotes endothelin (ET) generation through NAD(P)H oxidase-dependent production of reactive oxygen species. ET in turn induces metalloproteinase-mediated cleavage of pro-HBEGF and ectoshedding of HBEGF, which activates the EGFR and stimulates hBNP promoter activity. HBEGF also stimulates other phenotypic markers of hypertrophy including protein synthesis and sarcomeric assembly. The antioxidant N-acetylcysteine or the NAD(P)H oxidase inhibitor, apocynin, inhibited strain-dependent activation of the ET-1 promoter, HBEGF shedding, and hBNP promoter activation. The metalloproteinase inhibitor, GM-6001, prevented the induction of HBEGF ectoshedding and the hBNP promoter response to strain, suggesting a critical role for the metalloproteinase-dependent cleavage event in signaling the strain response. These findings suggest that metalloproteinase activity as an essential step in this pathway may prove to be a relevant therapeutic target in the management of cardiac hypertrophy.

Received for publication, August 20, 2003 , and in revised form, November 10, 2003.

^* This study was supported by a grants from the National Institutes of Health (HL35753) and The Research Evaluation and Allocation Committee at University of California (San Francisco, CA). 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.

Supported by a Senior Fellowship (Phase 1) from the Canadian Institutes of Health Research. Present address: St. Boniface Hospital Research Center, Faculty of Pharmacy, University of Manitoba, R4046, 351 Taché Ave., Winnipeg, Manitoba R2H 2A6, Canada.

^¶ To whom correspondence should be addressed. Tel.: 415-476-2729; Fax: 415-564-5813; E-mail: gardner{at}itsa.ucsf.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. P. Alibin, M. A. Kopilas, and H. D. I. Anderson Suppression of Cardiac Myocyte Hypertrophy by Conjugated Linoleic Acid: ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS {alpha} AND {gamma} J. Biol. Chem., April 18, 2008; 283(16): 10707 - 10715. [Abstract] [Full Text] [PDF]

				K. Y. Chung and J. W. Walker Interaction and Inhibitory Cross-Talk between Endothelin and ErbB Receptors in the Adult Heart Mol. Pharmacol., June 1, 2007; 71(6): 1494 - 1502. [Abstract] [Full Text] [PDF]

				J. Yoshioka, R. N. Prince, H. Huang, S. B. Perkins, F. U. Cruz, C. MacGillivray, D. A. Lauffenburger, and R. T. Lee Cardiomyocyte hypertrophy and degradation of connexin43 through spatially restricted autocrine/paracrine heparin-binding EGF PNAS, July 26, 2005; 102(30): 10622 - 10627. [Abstract] [Full Text] [PDF]

				M. Mendez and M. C. LaPointe PGE2-induced hypertrophy of cardiac myocytes involves EP4 receptor-dependent activation of p42/44 MAPK and EGFR transactivation Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2111 - H2117. [Abstract] [Full Text] [PDF]

				J.P. Dadoune, A. Pawlak, M.F. Alfonsi, and J.P. Siffroi Identification of transcripts by macroarrays, RT-PCR and in situ hybridization in human ejaculate spermatozoa Mol. Hum. Reprod., February 1, 2005; 11(2): 133 - 140. [Abstract] [Full Text] [PDF]