Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-[kappa ]B activation

Metabolism ◽  
2002 ◽  
Vol 51 (3) ◽  
pp. 327-333 ◽  
Author(s):  
Wolfgang Dichtl ◽  
Mikko P.S. Ares ◽  
Audrey Niemann J[ouml ]nson ◽  
Stefan Jovinge ◽  
Otmar Pachinger ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Linoleic Acid ◽  
Adhesion Molecule ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Vascular Adhesion

Lysophosphatidic Acid Activates Nuclear Factor Kappa B and Induces Proinflammatory Gene Expression in Endothelial Cells

1999 ◽  
Vol 82 (11) ◽  
pp. 1532-1537 ◽  
Author(s):  
Simon Robson ◽  
Volker Nehls ◽  
Alois Palmetshofer
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecule ◽  
Lysophosphatidic Acid ◽  
Nuclear Factor Kappa B ◽  
Intercellular Adhesion Molecule ◽  
Nuclear Factor ◽  
Intercellular Adhesion Molecule 1 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Nuclear Factor Kappa ◽  
Activated Platelets

SummaryThe cellular phospholipid, lysophosphatidic acid (LPA), released by activated platelets and fibroblasts or, at high levels, from ovarian and cervical carcinomas is a powerful serum mitogen that may modulate several signaling pathways in endothelial cells (EC). Hence, LPA could function in a paracrine manner during EC-platelet interactions at sites of vascular injury.Here, we demonstrate activation of the transcription factor nuclear factor kappa B (NF-κB) in EC following exposure to LPA. EC activation was further characterized by increased levels of mRNA transcripts encoding E-selectin, Intercellular Adhesion Molecule-1, Interleukin-8 and Monocyte Chemoattractant Protein-1. These effects were inhibited by preincubating EC either in the presence of mepacrine (to block phospholipase A2) or of pertussis toxin (to increase ADP-ribosylation of Gi proteins). No inhibition was observed in the presence of putative LPA receptor antagonists suramin or thrombospondin.LPA induces a proinflammatory activation of endothelial cells that (i) involves Gi proteins; (ii) depends on phospholipase A2 activity; (iii) is associated with the activation of NF-κB and (iv) results in increased expression of proinflammatory genes. We propose that LPA release by activated platelets may directly modulate vascular inflammatory responses. Abbreviations: EC, endothelial cells; LPA, lysophosphatidic acid; NF-κB, nuclear factor kappa B; PA, phosphatidic acid; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein-1, ICAM-1, intercellular adhesion molecule-1, vascular adhesion molecule-1; GAPDH, glycerol aldehyde phosphate dehydrogenase; MAPK, mitogen activated kinase, MEK, MAPK kinase, PAEC, porcine aortic EC.

scholarly journals Thrombin Stimulation of the Vascular Cell Adhesion Molecule-1 Promoter in Endothelial Cells Is Mediated by Tandem Nuclear Factor-κB and GATA Motifs

2001 ◽  
Vol 276 (50) ◽  
pp. 47632-47641 ◽  
Author(s):  
Takashi Minami ◽  
William C. Aird
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecule ◽  
Umbilical Vein ◽  
Fold Increase ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Mobility Shift ◽  
Response Element ◽  
Vascular Adhesion ◽  
Stimulation Of

The goal of this study was to delineate the transcriptional mechanisms underlying thrombin-mediated induction of vascular adhesion molecule-1 (VCAM-1). Treatment of human umbilical vein endothelial cells with thrombin resulted in a 3.3-fold increase in VCAM-1 promoter activity. The upstream promoter region of VCAM-1 contains a thrombin response element, two nuclear factor κB (NF-κB) motifs, and a tandem GATA motif. In transient transfection assays, mutation of the thrombin response element had no effect on thrombin induction. In contrast, mutation of either NF-κB site resulted in a complete loss of induction, whereas a mutation of the two GATA motifs resulted in a significant reduction in thrombin stimulation. In electrophoretic mobility shift assays, nuclear extracts from thrombin-treated endothelial cells displayed markedly increased binding to the tandem NF-κB and GATA motifs. The NF-κB complex was supershifted with anti-p65 antibodies, but not with antibodies to RelB, c-Rel, p50, or p52. The GATA complex was supershifted with antibodies to GATA-2, but not GATA-3 or GATA-6. A construct containing tandem copies of the VCAM-1 GATA motifs linked to a minimal thymidine kinase promoter was induced 2.4-fold by thrombin. Taken together, these results suggest that thrombin stimulation of VCAM-1 in endothelial cells is mediated by the coordinate action of NF-κB and GATA transcription factors.

scholarly journals Inhibition of protein kinase C beta phosphorylation activates nuclear factor-kappa B and improves postischemic recovery in type 1 diabetes

2020 ◽  
Vol 245 (9) ◽  
pp. 785-796
Author(s):  
Satyanarayana Alleboina ◽  
Thomas Wong ◽  
Madhu V Singh ◽  
Ayotunde O Dokun
Keyword(s):  
Endothelial Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
High Glucose ◽  
Nuclear Factor Kappa B ◽  
Nuclear Factor ◽  
Nuclear Factor Kappa ◽  
Kinase C ◽  
Protein Kinase C Beta

Peripheral artery disease (PAD) is a major health problem and is caused by atherosclerosis in arteries outside the heart leading to impaired blood flow. The presence of diabetes significantly increases the likelihood of having worse outcomes in PAD, and the molecular mechanisms involved are poorly understood. Hyperglycemia in diabetes activates the nuclear factor-kappa B (NF-κB) pathway, and chronic inflammation in diabetes is associated with vascular complications. Ischemia also activates NF-κB signaling that is important for perfusion recovery in experimental PAD. We hypothesized that prolonged exposure of endothelial cells to high glucose in diabetes impairs ischemic activation of the NF-κB pathway and contributes to poor perfusion recovery in experimental PAD. We assessed the effect of high glucose and ischemia on canonical and non-canonical NF-κB activation in endothelial cells and found both conditions activate both pathways. However, exposure of endothelial cells to high glucose impairs ischemia-induced activation of the canonical NF-κB pathway but not the non-canonical pathway. We probed an array of antibodies against signaling proteins in the NF-κB pathway to identify proteins whose phosphorylation status are altered in endothelial cells exposed to high glucose. Protein kinase C beta (PKCβ) was among the proteins identified, and its role in impaired ischemia-induced activation of NF-κB during hyperglycemia has not been previously described. Inhibition of PKCβ improves ischemia-induced NF-κB activation in vitroand in vivo. It also improves perfusion recovery in diabetic mice following experimental PAD. Thus, in diabetes, PKCβ phosphorylation contributes to impaired ischemic activation of NF-κB and likely a mechanism contributing to poor PAD outcomes. Impact statement Diabetes worsens the outcomes of peripheral arterial disease (PAD) likely in part through inducing chronic inflammation. However, in PAD, recovery requires the nuclear factor-kappa B (NF-κB) activation, a known contributor to inflammation. Our study shows that individually, both ischemia and high glucose activate the canonical and non-canonical arms of the NF-κB pathways. We show for the first time that prolonged high glucose specifically impairs ischemia-induced activation of the canonical NF-κB pathway through activation of protein kinase C beta (PKCβ). Accordingly, inhibition of PKCβ restores the ischemia-induced NF-κB activity both in vitroin endothelial cells and in vivoin hind limbs of type 1 diabetic mice and improves perfusion recovery after experimental PAD. Thus, this study provides a mechanistic insight into how diabetes contributes to poor outcomes in PAD and a potential translational approach to improve PAD outcomes.

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