Endothelin-1-specific Activation of B-type Natriuretic Peptide Gene via p38 Mitogen-activated Protein Kinase and Nuclear ETS Factors

Sampsa Pikkarainen,Heikki Tokola,Risto Kerkelä,Theresa Majalahti-Palviainen,Olli Vuolteenaho,Heikki Ruskoaho

doi:10.1074/jbc.m205616200

Abstract

Terminally differentiated cardiac myocytes adapt to mechanical and neurohumoral stress via morphological changes of individual cells accompanied by reactivation of fetal pattern of gene expression. Endothelin-1, a powerful paracrine mediator of myocyte growth, induces similar changes in cultured cardiac myocytes as those seen in hypertrophied heart in vivo. By using rat B-type natriuretic peptide promoter, we identified a novel ETS binding sequence, on which nuclear protein binding is activated in endothelin-1-treated cultured cardiac myocytes. This sequence binds ETS-like gene-1 transcription factor and mediates endothelin-1-specific activation of transcription, but not responses to increased calcium signaling via l-type calcium channels, angiotensin II treatment, or mechanical stretch of myocytes. Interestingly, endothelin-1 activated signaling converges via p38 mitogen-activated protein kinase-dependent mechanism on ETS binding site, whereas this element inhibits extracellular signal-regulated kinase activated transcription. In conclusion, given the fundamental role of the interaction of mitogen-activated protein kinases and ETS factors in regulation of eukaryotic cell differentiation, growth, and oncogenesis, these results provide the unique evidence of a endothelin-1- and mitogen-activated protein kinase-regulated ETS factor pathway for cardiac myocytes.

Highlights

Differentiated cardiac myocytes, due to their inability to divide, adapt to increased mechanical load and the activation of the neurohumoral system by hypertrophy
Cardiac myocytes subjected to ET-1 develop hypertrophy, including activation of protein synthesis [16, 20] and increased cell size accompanied by reorganization of sarcomeres (Fig. 1C)
To investigate this ET-1 responsive element further, we studied the complex formation of cardiac nuclear proteins with ETS binding sequence (EBS) of rat BNP (rBNP) promoter

Summary

Introduction

Differentiated cardiac myocytes, due to their inability to divide, adapt to increased mechanical load and the activation of the neurohumoral system by hypertrophy. By using rat B-type natriuretic peptide promoter, we identified a novel ETS binding sequence, on which nuclear protein binding is activated in endothelin-1-treated cultured cardiac myocytes.

Results

Conclusion