GATA-4 is a nuclear mediator of mechanical stretch-activated hypertrophic program.

Abstract

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 alpha-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.

• Authors: Sampsa Pikkarainen, Heikki Tokola, Theresa Majalahti-Palviainen, Risto Kerkela, Nina Hautala, Suparna S Bhalla, Férdéric Charron, Mona Nemer, Olli Vuolteenaho, Heikki Ruskoaho
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 26 Pg. 23807-16 (Jun 27 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12704188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• GATA4 Transcription Factor
• Nuclear Proteins
• RNA, Messenger
• Transcription Factor AP-1
• Transcription Factors
• Natriuretic Peptide, Brain
• Atrial Natriuretic Factor

Topics

• Animals
• Atrial Natriuretic Factor (genetics, physiology)
• DNA-Binding Proteins (genetics, physiology)
• GATA4 Transcription Factor
• Hypertrophy
• Mechanotransduction, Cellular
• Myocytes, Cardiac (cytology)
• Natriuretic Peptide, Brain
• Nuclear Proteins (genetics, physiology)
• Promoter Regions, Genetic
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Transcription Factor AP-1
• Transcription Factors (genetics, physiology)
• Transcriptional Activation