(Hypertension. 2000;35:188.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Endothelin-Dependent and -Independent Components of Strain-Activated Brain Natriuretic Peptide Gene Transcription Require Extracellular Signal Regulated Kinase and p38 Mitogen-Activated Protein Kinase
From the Metabolic Research Unit and Department of Medicine, University of California at San Francisco.
Correspondence to Dr David G. Gardner, Metabolic Research Unit, 1109 HSW, University of California at San Francisco, San Francisco, CA 94143-0540. E-mail gardner{at}itsa.ucsf.edu
Abstract—The application of mechanical strain to cultured cardiac myocytes in vitro leads to activation of the brain natriuretic peptide (BNP) gene promoter, a marker of cardiac hypertrophy. We have previously shown that this activation results from both a direct mechanostimulatory event and an indirect autocrine/paracrine stimulation involving the sequential production of angiotensin II and endothelin (ET). In the present study, we examined the role of p38 mitogen-activated protein kinase (MAPK) and extracellular signal regulated kinase (ERK) in signaling the increase in promoter activity trafficking through each of these pathways. ET was shown to stimulate both p38 MAPK and ERK activity in these cultures and to activate human BNP (hBNP) promoter activity. Activation of the promoter was inhibited 
45% by SB-203580, a p38 MAPK inhibitor, and 70% by PD98059, an inhibitor of the ERK-activating kinase MAPK kinase. The ET-independent (ie, direct) stimulation of the hBNP promoter by mechanical strain was inhibited 70% by SB-203580 and 60% by PD98059, implying that similar signaling circuitry is used, albeit to different degrees, by the direct and indirect pathways. The p38 MAPK component of both the ET-dependent and the ET-independent responses to strain appears to operate through a series of nuclear factor-
B binding, shear stress response element–like structures in the hBNP gene promoter. Collectively, these data suggest that activation of the BNP promoter by hypertrophic stimuli involves the participation of several independent signaling pathways. Such redundancy would help to guarantee generation of the full hypertrophic phenotype independently of the nature of the hypertrophic stimulus.
Key Words: stress, mechanical • endothelin • natriuretic peptides • protein kinases
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