Fluid shear stress activation of egr-1 transcription in cultured human endothelial and epithelial cells is mediated via the extracellular signal-related kinase 1/2 mitogen-activated protein kinase pathway.

Schwachtgen, Jean-Luc; Houston, Parul; Campbell, Callum J.; Sukhatme, Vikas P.; Braddock, Martin

doi:10.1172/jci1404

Cited by 181 publications

(147 citation statements)

References 63 publications

Supporting

Mentioning

130

Contrasting

Order By: Relevance

“…The consistent and dose-dependent up-regulation of FN protein production by airway epithelial cells undergoing normal stresses highlights the relevance of mechanical stress in asthma as contributing to the associated changes in the airway wall. Our data also support other studies demonstrating that Egr-1 is stimulated by mechanical stress (11,19,20).…”

Section: Discussionsupporting

confidence: 92%

“…Egr-1 is a mechanically responsive gene (11,19,20) that encodes a transcription factor capable of modulating a number of genes that regulate fibroblast recruitment, proliferation, and activation [e.g., transforming growth factor-␤, platelet-derived growth factor-A, FN, and tumor necrosis factor-␣ (21,22)]. Fibronectin was chosen as a response indicator for a number of reasons.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Swartz

Tschumperlin

Kamm

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

241

158

View full text Add to dashboard Cite

Tissue remodeling often reflects alterations in local mechanical conditions and manifests as an integrated response among the different cell types that share, and thus cooperatively manage, an extracellular matrix. Here we examine how two different cell types, one that undergoes the stress and the other that primarily remodels the matrix, might communicate a mechanical stress by using airway cells as a representative in vitro system. Normal stress is imposed on bronchial epithelial cells in the presence of unstimulated lung fibroblasts. We show that (i) mechanical stress can be communicated from stressed to unstressed cells to elicit a remodeling response, and (ii) the integrated response of two cell types to mechanical stress mimics key features of airway remodeling seen in asthma: namely, an increase in production of fibronectin, collagen types III and V, and matrix metalloproteinase type 9 (MMP-9) (relative to tissue inhibitor of metalloproteinase-1, TIMP-1). These observations provide a paradigm to use in understanding the management of mechanical forces on the tissue level.airway wall remodeling ͉ airway epithelium ͉ asthma ͉ lung fibroblasts I n the past two decades, it has been well established that many cells are sensitive to mechanical forces and can change their phenotype and surrounding extracellular matrix (ECM) in response to changes in their mechanical environment. However, it has not been established how mechanical forces are managed on a tissue level, in which different cell types share a common ECM and may alter their mechanical environment by inducing other cells to remodel the ECM.The airway wall is an example of a mechanically active tissue (e.g., bronchoconstriction) composed of multiple cell types that share a common extracellular matrix. It is known that patients with poorly controlled asthma develop structural changes in the airway wall: the subepithelial layers significantly thicken (1-4) and there is deposition of collagen types III and V, among other fibrous proteins, beneath the basement membrane (4, 5). The major consequences of airway remodeling are altered tissue mechanics and airway hyperresponsiveness (6).The remodeling process in asthma has been attributed to the effects of the inflammatory response that characterizes the disease, but this sequence of events has only been inferentially established. We propose an alternative hypothesis for airway wall remodeling in asthma, namely that the mechanical stress associated with bronchoconstriction that is imposed on bronchial epithelial cells could, itself, stimulate and amplify airway wall remodeling in the absence of inflammatory agents. Specifically, we hypothesize that, when airway epithelial cells are subjected to mechanical stress, they act in concert with subepithelial fibroblasts to modulate the fibrous structure of the airway in response to this mechanical stress.This hypothesis, if true, would provide two key insights. First, it would challenge the idea that airway wall remodeling in asthma is solely the consequence of inflam...

show abstract

Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Swartz

Tschumperlin

Kamm

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

241

158

View full text Add to dashboard Cite

show abstract

“…Nonetheless, in view of the importance of tissue factor for initiating coagulation, its expression in the intravascular space is of significance and serves as an appropriate starting point for analyzing roles of PKC␤II and Egr-1 in ischemic stress. There are intriguing parallels between our results concerning Egr-1 expression and activation using hypoxia as the stimulus and observations of others concerning the role of Egr-1 in the cellular response to urea and shear stress (23,47).…”

Section: Discussionsupporting

confidence: 87%

Hypoxia-associated Induction of Early Growth Response-1 Gene Expression

Yan¹,

Lu²,

Zou³

et al. 1999

Journal of Biological Chemistry

236

187

View full text Add to dashboard Cite

1998) Proc. Natl. Acad. Sci. U. S. A. 95, 8298 -8303). Now, we show that cultured monocytes subjected to hypoxia (pO 2 Ϸ 12 torr) displayed increased Egr-1 expression because of de novo biosynthesis, with a Ϸ10-fold increased rate of transcription. Transfection of monocytes with Egr-1 promoter-luciferase constructs localized elements responsible for hypoxia-enhanced expression to ؊424/؊65, a region including EBS (ets binding site)-SRE (serum response element)-EBS and SRE-EBS-SRE sites. Further studies with each of these regions ligated to the basal thymidine kinase promoter and luciferase demonstrated that EBS sites in the element spanning ؊424/؊375 were critical for hypoxia-enhanceable gene expression. These data suggested that an activated ets factor, such as Elk-1, in complex with serum response factor, was the likely proximal trigger of Egr-1 transcription. Indeed, hypoxia induced activation of Elk-1, and suppression of Elk-1 blocked up-regulation of Egr-1 transcription. The signaling cascade preceding Elk-1 activation in response to oxygen deprivation was traced to activation of protein kinase C-␤II, Raf, mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase and mitogen-activated protein kinases. Comparable hypoxiamediated Egr-1 induction and activation were observed in cultured hepatoma-derived cells deficient in HIF-1␤ and wild-type hepatoma cells, indicating that the HIF-1 and Egr-1 pathways are initiated independently in response to oxygen deprivation. We propose that activation of Egr-1 in response to hypoxia induces a different facet of the adaptive response than HIF-1, one component of which causes expression of tissue factor, resulting in fibrin deposition.

show abstract

“…Activation and transportation of immediate early response genes such as cfos and transcription factor NF-κB, which can bind to mechanoresponsive ECM genes, are suggested as two of the primary responses to mechanical loads (Khachigian et al, 1995;Sadoshima and Izumo, 1997;Mercurio and Manning, 1999a,b;Chen et al, 2003;Xiao, 2004). Transcription and synthesis of nuclear factors such as early growth response-1 (EGR-1) that can transactivate a specific ECM gene are considered secondary responses to mechanical loads (Schwachtgen et al, 1998;. Finally, mechanisms that include triggering autocrine or paracrine release of growth factors such as TGF-β by mechanical loads to regulate the transcription of "mechanoresponsive genes" are also presented (Davies et al, 1997;Sadoshima and Izumo, 1997).…”

Section: Cellular Mechanotransductionmentioning

confidence: 99%

Mechanoregulation of gene expression in fibroblasts

Wang

Thampatty

Lin

et al. 2007

Gene

227

187

View full text Add to dashboard Cite

Mechanical loads placed on connective tissues alter gene expression in fibroblasts through mechanotransduction mechanisms by which cells convert mechanical signals into cellular biological events, such as gene expression of extracellular matrix components (e.g., collagen). This mechanical regulation of ECM gene expression affords maintenance of connective tissue homeostasis. However, mechanical loads can also interfere with homeostatic cellular gene expression and consequently cause the pathogenesis of connective tissue diseases such as tendinopathy and osteoarthritis. Therefore, the regulation of gene expression by mechanical loads is closely related to connective tissue physiology and pathology. This article reviews the effects of various mechanical loading conditions on gene regulation in fibroblasts and discusses several mechanotransduction mechanisms. Future research directions in mechanoregulation of gene expression are also suggested.

show abstract

Fluid shear stress activation of egr-1 transcription in cultured human endothelial and epithelial cells is mediated via the extracellular signal-related kinase 1/2 mitogen-activated protein kinase pathway.

Cited by 181 publications

References 63 publications

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Mechanical stress is communicated between different cell types to elicit matrix remodeling

Hypoxia-associated Induction of Early Growth Response-1 Gene Expression

Mechanoregulation of gene expression in fibroblasts

Contact Info

Product

Resources

About