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J. Biol. Chem., Vol. 278, Issue 26, 23807-23816, June 27, 2003

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GATA-4 Is a Nuclear Mediator of Mechanical Stretch-activated Hypertrophic Program^*

Sampsa Pikkarainen  , Heikki Tokola  , Theresa Majalahti-Palviainen ¶, Risto Kerkelä , Nina Hautala , Suparna S. Bhalla ||, Frédéric Charron ||, Mona Nemer ||, Olli Vuolteenaho ¶ and Heikki Ruskoaho  **

From the Department of Pharmacology and Toxicology and ^¶Department of Physiology, Biocenter Oulu, University of Oulu, P. O. Box 5000, FIN-90014 University of Oulu, Finland and ^||Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec H2W 1R7, Canada

In overloaded heart the cardiomyocytes adapt to increased mechanical and neurohumoral stress by activation of hypertrophic program, resulting in morphological changes of individual cells and specific changes in gene expression. Accumulating evidence suggests an important role for the zinc finger transcription factor GATA-4 in hypertrophic agonist-induced cardiac hypertrophy. However, its role in stretch-induced cardiomyocyte hypertrophy is not known. We employed an in vitro mechanical stretch model of cultured cardiomyocytes and used rat B-type natriuretic peptide promoter as stretch-sensitive reporter gene. Stretch transiently increased GATA-4 DNA binding activity and transcript levels, which was followed by increases in the expression of B-type natriuretic peptide as well as atrial natriuretic peptide and skeletal -actin genes. The stretch inducibility mapped primarily to the proximal 520 bp of the B-type natriuretic peptide promoter. Mutational studies showed that the tandem GATA consensus sites of the proximal promoter in combination with an Nkx-2.5 binding element are critical for stretch-activated B-type natriuretic peptide transcription. Inhibition of GATA-4 protein production by adenovirus-mediated transfer of GATA-4 antisense cDNA blocked stretch-induced increases in B-type natriuretic peptide transcript levels and the sarcomere reorganization. The proportion of myocytes with assembled sarcomeres in control adenovirus-infected cultures increased from 14 to 59% in response to stretch, whereas the values for GATA-4 antisense-treated cells were 6 and 13%, respectively. These results show that activation of GATA-4, in cooperation with a factor binding on Nkx-2.5 binding element, is essential for mechanical stretch-induced cardiomyocyte hypertrophy.

Received for publication, March 17, 2003 , and in revised form, April 14, 2003.

^* This work was supported by grants from Academy of Finland (to H. R.), The National Technology Foundation TEKES (to H. R.), the Sigrid Juselius Foundation (to H. R.), the Aarne Koskelo Foundation (to H. T., S. P., and T. M.-P.), the Ida Montin Foundation (to H. T. and S. P.), the Finnish Foundation for Cardiovascular Research (to S. P. and H. R.), the Finnish Cultural Foundation (to S. P. and T. M.-P.), the Paulo Foundation (to H. T.), the Research Foundation of Pharmacal (to H. T.), the Finnish Medical Society (to H. T.), the Emil Aaltonen Foundation (to S. P. and T. M.-P.), and by the Canadian Institutes of Health Research (to M. N.). 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.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Faculty of Medicine, Biocenter Oulu, University of Oulu, P.O. Box 5000 (Aapistie 5), FIN-90014 University of Oulu, Finland. Tel.: 358-8-5375236; Fax: 358-8-5375247; E-mail: heikki.ruskoaho{at}oulu.fi.

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