Endothelin-Dependent and -Independent Components of Strain-Activated Brain Natriuretic Peptide Gene Transcription Require Extracellular Signal Regulated Kinase and p38 Mitogen-Activated Protein Kinase

Abstract

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 Ϸ45% by SB-203580, a p38 MAPK inhibitor, and Ϸ70% 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 Ϸ70% by SB-203580 and Ϸ60% 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.

Angiotensin-(1–7) inhibits growth of cardiac myocytes through activation of themasreceptor

“…The transfection of constitutively active MEK1 augmented atrial natriuretic factor promoter activity in cultured myocytes, whereas a dominant-negative MEK1 construct attenuated its activity (20). Furthermore, the MEK1 inhibitor PD-98059 reduced agonistinduced natriuretic promoter activity in cardiac cells (29). Transgenic mice containing an activated MEK1 cDNA exhibited a phenotype of compensated cardiac hypertrophy (8).…”

Activation of Cardiac c-Jun NH 2 -Terminal Kinases and p38-Mitogen–Activated Protein Kinases With Abrupt Changes in Hemodynamic Load

“…15,16 The activation of multiple parallel MAPK pathways is sufficient to induce several marker genes for cardiac hypertrophy, such as brain natriuretic peptide, in cultures of neonatal cardiac myocytes. 17 The application of mechanical strain to cultured neonatal cardiac myocytes on a deformable matrix has been shown to induce JNK activation. 18 In the perfused adult rat heart, JNKs are activated by ischemia/reperfusion and by reactive oxygen species, and rapid phosphorylation of p38 is observed in the perfused heart by ischemia, ischemia/reperfusion, and highpressure perfusion.…”

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

“…1A), ofwhichBNPsynthesiswasaugmentedthroughanET A receptordependent mechanism (Fig. 1B) (23). In addition, 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.…”