Transcriptional Activation of the Zinc Finger Transcription Factor BTEB2 Gene by Egr-1 Through Mitogen-Activated Protein Kinase Pathways in Vascular Smooth Muscle Cells

Kawai-Kowase, Keiko; Kurabayashi, Masahiko; Hoshino, Yoichi; Ohyama, Yoshio; Nagai, Ryozo

doi:10.1161/01.res.85.9.787

Cited by 88 publications

(96 citation statements)

References 46 publications

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“…It has also been reported that AT2R inhibits the activity of ERK. Several observations indicate that the ERK pathway activates the BTeB2 promoter (29). The present study found that the inhibition of ERK1/2 is linked to the downregulation of BTEB2.…”

Section: Discussionsupporting

confidence: 70%

Overexpression of angiotensin II type 2 receptor suppresses neointimal hyperplasia in a rat carotid arterial balloon injury model

Tang

Yang

et al. 2011

Mol Med Rep

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Abstract. angiotensin ii (anG ii) type 2 receptor (aT2r) has been recognized to suppress the proliferation of vascular smooth muscle cells (VSMcs). The aim of the present study was to determine whether aT2r overexpression inhibits neointimal hyperplasia in a rat carotid arterial balloon injury model and to examine the underlying mechanisms of its activity. Balloon-injured rats receiving ad-aT2r showed significant diminutions in neointimal area and intima/ media ratio compared to non-treated rats or rats receiving adenovirus containing green fluorescent protein (Ad-GFP). In addition, extracellular regulated kinase 1/2 (ERK1/2) and basic transcription element-binding protein 2 (BTeB2) were significantly down-regulated in the arteries and VSMCs of Ad-AT2R-treated rats and compared to Ad-GFP-treated rats. However, ad-aT2r transfection failed to affect the expression of anG ii type 1 receptor (aT1r) in carotid arteries and cultured VSMcs. The present study provides direct evidence that AT2R plays a beneficial role in balloon injury-induced neointimal hyperplasia, which is mainly attributed to the inhibition of VSMc proliferation and involves the down-regulation of the ERK1/2 and BTEB2 pathways, but is independent of the expression of aT1r. IntroductionPercutaneous transluminal balloon angioplasty is widely used for the treatment of obstructed atherosclerotic vascular diseases (1). However, balloon injury to the arterial wall induced by restenosis limits its overall benefits (2). Despite dramatic advances in reducing the incidence of restenosis by drug-eluting stents, it remains a considerable medical challenge (3-5). The major pathological process underlying restenosis is neointimal hyperplasia (6), which results from the phenotypic modulation, proliferation, migration and extracellular matrix synthesis of vascular smooth muscle cells (VSMcs) (7).release of angiotensin ii (anG ii) in response to vascular injury plays an important role in neointimal hyperplasia through the stimulation of VSMc proliferation and migration (8,9). Two distinct subtypes of anG ii receptors, type 1 (AT1R) and type 2 (AT2R), have been identified. The proliferation effect of anG ii has been attributed to aT1r (10,11). additionally, treatment with aT1r blockers (arBs) reduces the incidence of restenosis (12,13). aT2r is expressed abundantly in the fetal vasculature with rapid decline after birth, and is re-expressed in the adult vasculature under certain pathological cardiovascular conditions, such as vessel injury and inflammation (14,15). In injured vessels, aT1r is highly expressed, while aT2r is expressed at low levels (16). Furthermore, it has been reported that aT2r has anti-proliferation, anti-migration and proapoptotic effects on VSMcs in vitro, and antagonizes the growth effect of aT1r (17,18). These lines of evidence suggest that aT2r plays a crucial role in the neointimal hyperplasia response to vascular injury.in this study, we investigated the effects of the overexpression of aT2r by adenoviral gene transfer on neointimal hyperpla...

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Section: Discussionsupporting

confidence: 70%

Overexpression of angiotensin II type 2 receptor suppresses neointimal hyperplasia in a rat carotid arterial balloon injury model

Tang

Yang

et al. 2011

Mol Med Rep

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“…survivin) [74] or proproliferative pathways (e.g. mitogen-activated protein kinases) [75] that are activated following vessel injury can, in turn, augment KLF5 expression. These key observations suggest that KLF5 may be an important regulator of the SMCs response to vascular injury.…”

Section: Klf5mentioning

confidence: 99%

Kruppel-like Factors (KLFs) in muscle biology

Haldar¹,

Ibrahim²,

Jain³

2007

Journal of Molecular and Cellular Cardiology

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The Kruppel-like Factor (KLF) family of zinc-finger transcription factors are critical regulators of cell differentiation, phenotypic modulation and physiologic function. An emerging body of evidence implicates an important role for these factors in cardiovascular biology, however, the role of KLFs in muscle biology is only beginning to be understood. This article reviews the published data describing the role of KLFs in cardiomyocytes, smooth muscle cells, and skeletal muscle and highlights the importance of these factors in cardiovascular development, physiology and disease pathobiology.

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“…For example, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were shown to be potent activators of KLF5 in vitro (Kawai-Kowase et al, 1999;Hoshino et al, 2000;Ogata et al, 2000). Activation of KLF5 expression has also been linked to the Wnt/Wg signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Krüppel-like factor 5 mediates the transforming activity of oncogenic H-Ras

et al. 2004

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Previous studies indicate that Kru¨ppel-like factor 5 (KLF5), also known as intestinal-enriched Kru¨ppel-like factor (IKLF), is a positive regulator of cell proliferation and gives rise to a transformed phenotype when overexpressed. Here we demonstrate that levels of KLF5 transcript and protein are significantly elevated in oncogenic H-Ras-transformed NIH3T3 cells. These cells display an accelerated rate of proliferation in both serum-containing and serum-deprived media and form anchorage-independent colonies in soft agar assays. H-Ras-transformed cells also contain elevated mitogenactivated protein kinase (MAPK) activity. When treated with inhibitors of MEK (MAPK kinase), H-Ras-transformed cells lose their growth advantage and no longer form colonies. Significantly, levels of KLF5 transcript and protein are substantially reduced in H-Ras-transformed cells treated with MEK inhibitors. Moreover, inhibition of KLF5 expression in H-Ras-transformed cells with KLF5-specific small interfering RNA (siRNA) leads to a decreased rate of proliferation and a significant reduction in colony formation. H-Ras-transformed cells also contain elevated levels of Egr1 that are diminished by MEK inhibitors. Inhibition of Egr1 by siRNA results in a reduced level of KLF5, indicating that Egr1 mediates the inductive action of MAPK on KLF5. Lastly, KLF5 activates expression of cyclin D1. These findings indicate that the increased expression of KLF5 in H-Rastransformed cells is secondary to increased MAPK activity from H-Ras overexpression and that the elevated level of KLF5 is in part responsible for the proproliferative and transforming activities of oncogenic H-Ras.

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Transcriptional Activation of the Zinc Finger Transcription Factor BTEB2 Gene by Egr-1 Through Mitogen-Activated Protein Kinase Pathways in Vascular Smooth Muscle Cells

Cited by 88 publications

References 46 publications

Overexpression of angiotensin II type 2 receptor suppresses neointimal hyperplasia in a rat carotid arterial balloon injury model

Overexpression of angiotensin II type 2 receptor suppresses neointimal hyperplasia in a rat carotid arterial balloon injury model

Kruppel-like Factors (KLFs) in muscle biology

Krüppel-like factor 5 mediates the transforming activity of oncogenic H-Ras

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