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PMID:19193866

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Citation

Sen, U, Tyagi, N, Patibandla, PK, Dean, WL, Tyagi, SC, Roberts, AM and Lominadze, D (2009) Fibrinogen-induced endothelin-1 production from endothelial cells. Am. J. Physiol., Cell Physiol. 296:C840-7

Abstract

We previously demonstrated that fibrinogen (Fg) binding to the vascular endothelial intercellular adhesion molecule-1 (ICAM-1) leads to microvascular constriction in vivo and in vitro. Although a role of endothelin-1 (ET-1) in this Fg-induced vasoconstriction was suggested, the mechanism of action was not clear. In the current study, we tested the hypothesis that Fg-induced vasoconstriction results from ET-1 production by vascular endothelial cells (EC) and is mediated by activation of extracellular signal-regulated kinase -1/2 (ERK-1/2). Confluent, rat heart microvascular endothelial cells (RHMECs) were treated with one of the following: Fg (2 or 4 mg/ml), Fg (4 mg/ml) with ERK-1/2 kinase inhibitors (PD-98059 or U-0126), Fg (4 mg/ml) with an antibody against ICAM-1, or medium alone for 45 min. The amount of ET-1 formed and the concentration of released von Willebrand factor (vWF) in the cell culture medium were measured by ELISAs. Fg-induced exocytosis of Weibel-Palade bodies (WPBs) was assessed by immunocytochemistry. Phosphorylation of ERK-1/2 was detected by Western blot analysis. Fg caused a dose-dependent increase in ET-1 formation and release of vWF from the RHMECs. This Fg-induced increase in ET-1 production was inhibited by specific ERK-1/2 kinase inhibitors and by anti-ICAM-1 antibody. Immunocytochemical staining showed that an increase in Fg concentration enhanced exocytosis of WPBs in ECs. A specific endothelin type B receptor blocker, BQ-788, attenuated the enhanced phosphorylation of ERK-1/2 in ECs caused by increased Fg content in the culture medium. The presence of an endothelin converting enzyme inhibitor, SM-19712, slightly decreased Fg-induced phosphorylation of ERK-1/2, but inhibited production of Fg-induced ET-1 production. These results suggest that Fg-induced vasoconstriction may be mediated, in part, by activation of ERK-1/2 signaling and increased production of ET-1 that further increases EC ERK-1/2 signaling. Thus, an increased content of Fg may enhance vasoconstriction through increased production of ET-1.

Links

PubMed PMC2670653 Online version:10.1152/ajpcell.00515.2008

Keywords

Animals; Aspartic Acid Endopeptidases/antagonists & inhibitors; Aspartic Acid Endopeptidases/metabolism; Butadienes/pharmacology; Cells, Cultured; Coronary Vessels/metabolism; Endothelial Cells/drug effects; Endothelial Cells/enzymology; Endothelial Cells/metabolism; Endothelin B Receptor Antagonists; Endothelin-1/metabolism; Exocytosis; Fibrinogen/metabolism; Flavonoids/pharmacology; Humans; Intercellular Adhesion Molecule-1/metabolism; Metalloendopeptidases/antagonists & inhibitors; Metalloendopeptidases/metabolism; Microvessels/metabolism; Mitogen-Activated Protein Kinase 1/antagonists & inhibitors; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/antagonists & inhibitors; Mitogen-Activated Protein Kinase 3/metabolism; Nitriles/pharmacology; Oligopeptides/pharmacology; Phosphorylation; Piperidines/pharmacology; Protein Kinase Inhibitors/pharmacology; Rats; Receptor, Endothelin B/metabolism; Sulfonamides/pharmacology; Sulfonylurea Compounds/pharmacology; Vasoconstriction; Weibel-Palade Bodies/metabolism; von Willebrand Factor/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FIBG

involved_in

GO:0090277: positive regulation of peptide hormone secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P05305)
  • occurs_in:(CL:0000115)

Seeded From UniProt

complete

HUMAN:FIBG

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBG

involved_in

GO:0050714: positive regulation of protein secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P04275)
  • occurs_in:(CL:0000115)

Seeded From UniProt

complete

HUMAN:FIBG

involved_in

GO:0045921: positive regulation of exocytosis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBA

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBA

involved_in

GO:0050714: positive regulation of protein secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P04275)
  • occurs_in:(CL:0000115)

Seeded From UniProt

complete

HUMAN:FIBA

involved_in

GO:0045921: positive regulation of exocytosis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBA

involved_in

GO:0090277: positive regulation of peptide hormone secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P05305)
  • occurs_in:(CL:0000115)

Seeded From UniProt

complete

HUMAN:FIBB

involved_in

GO:0045921: positive regulation of exocytosis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBB

involved_in

GO:0050714: positive regulation of protein secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P04275)
  • occurs_in:(CL:0000115)

Seeded From UniProt

complete

HUMAN:FIBB

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FIBB

involved_in

GO:0090277: positive regulation of peptide hormone secretion

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P05305)
  • occurs_in:(CL:0000115)

Seeded From UniProt

complete

Notes

See also

References

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