Regulation of Vascular Smooth Muscle Cell Proliferation by Nuclear Factor-κB and Its Inhibitor, I-κB

Hoshi, Sachi; Goto, Masaki; Koyama, Noriyuki; Nomoto, Ken’ichi; Tanaka, Hiroshi

doi:10.1074/jbc.275.2.883

Cited by 93 publications

(69 citation statements)

References 65 publications

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“…Although we have yet to elucidate the mechanisms responsible for CD40-mediated proliferation of IHEC, results from our present study ( Figure 9B) indicate that NF-B does play a key role in regulating this process. Indeed, the NF-B family of transcription factors has been shown to regulate proliferation in several cell types (Hoshi et al, 2000;Brantley et al, 2001;Lim et al, 2001). Endothelial cell proliferation in response to CD40 could be important not only in chronic inflammation but also in angiogenesis and tumor vascularization where 60% of hepatocellular carcinomas express high levels of CD40 (Sugimoto et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Choudhury

Russell

Randhawa

et al. 2003

MBoC

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CD40, a tumor necrosis factor receptor superfamily member, is up-regulated on intraheptatic endothelial cells (IHEC) and epithelial cells during inflammatory liver disease, and there is evidence that the functional outcome of CD40 ligation differs between cell types. Ligation of CD40 on cholangiocytes or hepatocytes results in induction of Fas-mediated apoptosis, whereas ligation of IHEC CD40 leads to enhanced chemokine secretion and adhesion molecule expression. We now report that differential activation of two transcription factors, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), in primary human hepatocytes or IHEC, is associated with and may explain, in part, the different responses of these cell types to CD40 ligation. CD40 ligation induced a rise in NF-κB activity in hepatocytes ,which peaked at 2 h and returned to baseline by 24 h; however, IHEC CD40 ligation resulted in a sustained up-regulation of NF-κB (>24 h). In hepatocytes, CD40 ligation led to sustained up-regulation of AP-1 activity >24 h associated with increased protein levels of RelA (p65), c-Jun, and c-Fos, whereas no induction of AP-1 activity was observed in IHECs. Analysis of mitogen-activated protein kinase phosphorylation (phospho-extracellular signal-regulated kinase 1/2 and phospho-c-Jun NH2-terminal kinase 1/2) and expression of inhibitor κBα were entirely consistent, and thus confirmed the profiles of NF-κB and AP-1 signaling and the effects of the selective inhibitors assessed using electrophoretic mobility shift assay or Western immunoblotting. CD40 ligation resulted in induction of apoptosis in hepatocytes after 24 h, but on IHECs, CD40 ligation resulted in proliferation. Inhibition of (CD40-mediated) NF-κB activation prevented IHEC proliferation and led to induction of apoptosis. Selective extracellular signal-regulated kinase and c-Jun NH2-terminal kinase inhibitors reduced levels of apoptosis in (CD40-stimulated) hepatocytes by ∼50%. We conclude that differential activation of these two transcription factors in response to CD40 ligation is associated with differences in cell fate. Transient activation of NF-κB and sustained AP-1 activation is associated with apoptosis in hepatocytes, whereas prolonged NF-κB activation and a lack of AP-1 activation in IHECs result in proliferation.

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Section: Discussionmentioning

confidence: 99%

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Choudhury

Russell

Randhawa

et al. 2003

MBoC

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“…Receptor-mediated actions of thrombin enhance the expression of inflammatory cytokines and chemokines and are associated with pathological conditions such as atherosclerosis and restenosis after vascular interventions (43,44). Activation of PAR-1 by thrombin also enhances NF-κB activation in endothelial cells (45) and VSMCs (46). Because upregulation of these cytokines and chemokines that contribute to the promotion of vascular remodeling (47-50) is known to enhance NF-κB activation, there is a possibility that the action of thrombin on migration and proliferation of cells in the vascular wall is mediated by its stimulatory effect on the expression of inflammatory cytokines and chemokines.…”

Section: Discussionmentioning

confidence: 99%

Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II–deficient mice

Aihara¹,

Azuma²,

Akiyama³

et al. 2007

J. Clin. Invest.

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atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII -/-mice were embryonically lethal. In HCII +/-mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-1-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII +/-mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII +/-mice. The intimal hyperplasia in HCII +/-mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.

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“…C, integration of G-protein signaling pathways originating from activation of PAR-1 by thrombin ultimately regulate the expression of THBS1 via sequential expression of MYC and EGR1. Initially, NF␤ is activated via a G q -mediated pathway, resulting in the up-regulation of MYC (83)(84)(85)(86)(87)(88)(89)(90)(91). EGR1 is up-regulated by activation of extracellular signal-regulated kinase (ERK) via G␤␥ and/or protein kinase Cdependent (PKC) pathways (53,54,75,(77)(78)(79)92).…”

Section: Regulation Of Thbs1 Gene Expression By Thrombin Inmentioning

confidence: 99%

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells

McLaughlin¹,

Mazzoni

Cleator

et al. 2005

Journal of Biological Chemistry

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Regulation of Vascular Smooth Muscle Cell Proliferation by Nuclear Factor-κB and Its Inhibitor, I-κB

Cited by 93 publications

References 65 publications

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Differential Induction of Nuclear Factor-κB and Activator Protein-1 Activity after CD40 Ligation Is Associated with Primary Human Hepatocyte Apoptosis or Intrahepatic Endothelial Cell Proliferation

Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II–deficient mice

Thrombin Modulates the Expression of a Set of Genes Including Thrombospondin-1 in Human Microvascular Endothelial Cells

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