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

Summary

The 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 G_i 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 G_i 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.

Keywords

Lysophosphatidic acid - nuclear factor kappa B - transcription factor - inflammation - endothelial cells - platelets - gene expression

• References

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