Mechanical strain activates BNP gene transcription through a p38/NF-κB–dependent mechanism

Abstract

IntroductionSustained hemodynamic overload elicits a series of functional and structural changes in the ventricular myocyte that culminate in cardiac hypertrophy. This is viewed as a compensatory response that, over the short term, results in improved cardiac performance; however, protracted exposure to the hypertrophic stimulus often results in an alteration in phenotype that leads to progressive heart failure. Clinical hypertrophy has, in fact, been linked to increased mortality independent of associated cardiovascular risk factors (1).At the cellular level, hypertrophy is thought to develop in response to a combination of mechanical (i.e., load-dependent) and neurohumoral stimuli, such as angiotensin II (AII), endothelin (ET), and adrenergic agonists. In cultured neonatal rat cardiac myocytes, both mechanical (2-4) and biochemical (5-8) stimuli effect a series of changes in gene expression that closely parallel those seen in the hypertrophied heart in vivo (9). This includes the sequential activation of immediate early genes (e.g., protooncogenes like c-jun, c-fos, and c-myc), a fetal gene program (e.g., atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP], skeletal α-actin, and β-myosin heavy chain) that is typically quiescent in the nonhypertrophied adult ventricular myocardium, and the structural sarcomeric genes that contribute the protein infrastructure associated with hypertrophy (e.g., cardiac α-actin and myosin light chain-2) (9).The signaling cascades underlying the hypertrophic phenotype remain only partially understood. Protein kinase C (10), calcium/calmodulin (11), calcineurin (12-13), nonreceptor protein tyrosine kinases (14, 15), the Janus kinase/STAT system (16, 17), small G proteins (e.g., Ras, Rac, Rho, Cdc42) (18-21), and the various mitogen-activated protein kinases (i.e., ERKs, JNKs, and p38 MAPKs) (22-38) have each been implicated as playing a role in signaling hypertrophy. The MAPKs in particular have been the focus of considerable attention. Hypertrophic stimuli have been shown to activate ERK (22-24), JNK (30, 32), and p38 (34, 37, 38) in either cultured ventricular myocytes or intact myocardial tissue. Whereas interference with the ERK pathway has been shown to block some aspects of hypertrophy-dependent gene expression, it does not affect the morphological changes accompanying hypertrophy (27); in some instances (29) it has been dissociated from the hypertrophic program completely. JNKs have also been linked to hypertrophy (28-32), although recent studies have raised questions about the importance of these kinases in signaling various aspects of the phenotype (37). Activation of p38 by upstream kinases (e.g., MKK6) (35) or hypertrophic agonists (38) has been associated with effects on myocyte growth. Of note, the nature of the effect appears to be isoform specific. Overexpression of activated MKK3 (MKK3bE) elicited both characteristic hypertrophic changes and increased apoptosis in ade- Application of mechanical strain to neonatal rat ventricular myocytes in culture evo...

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…GATA4 is phosphorylated at Ser105 by both ERK and p38,21, 22, 23 regulating its DNA‐binding activity and transcriptional activity 22, 23, 24, 25, 26. In addition to GATA4, a number of other transcriptional regulators, such as nuclear factor of activated T‐cells (NFAT), NKX‐2.5, Elk‐1, activator protein 1, myocardin, serum response factor, and nuclear factor kappa B, have been shown to participate in transcriptional regulation of BNP 20, 27, 28, 29, 30, 31, 32. Several studies have also indicated a central role for M‐CAT element, a thyroid‐responsive element and shear stress‐responsive element on the BNP promoter regulating BNP transcriptional activity 33, 34, 35, 36.…”

Osteopontin Gene Regulation by Oscillatory Fluid Flow via Intracellular Calcium Mobilization and Activation of Mitogen-activated Protein Kinase in MC3T3–E1 Osteoblasts

“…Recently MAPK family members including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAP kinase have been shown to be important signaling components linking mechanical stimuli to cellular responses, including cell growth, differentiation, and metabolic regulation, in endothelial cells, smooth muscle cells, and myocytes (27)(28)(29)(30). However, the role of MAPKs in bone cell mechanotransduction has not been determined.…”

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

“…11 From a mechanotransduction standpoint, strain has been shown to activate ERKs, JNKs, and p38 MAPKs in these myocyte cultures, [7][8][9][10] with the latter (ie, p38 MAPK) accounting for Ϸ50% of the composite hBNP promoter response. 12 This activity depends on interaction of the transcription factor nuclear factor (NF)-B with 3 shear stress response element (SSRE)-like structures in the proximal hBNP promoter.…”