cs1-peptide and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine

Previous studies have demonstrated the importance of endothelial apical expression of connecting segment-1 (CS-1) fibronectin in mediating the entry of monocytes into atherosclerotic lesions and other sites of chronic inflammation. We previously demonstrated that oxidized PAPC (OxPAPC) increases monocyte-specific binding to arterial endothelium by causing deposition of CS-1 fibronectin on apical alpha5beta1 integrin. The present studies identify important signal transduction components regulating this pathway.. Using endothelial cells in culture, we demonstrate that activation of R-Ras is responsible for CS-1-mediated monocyte binding. Although few natural activators of R-Ras have been demonstrated, OxPAPC activated endothelial R-Ras by 2.5-fold but decreased levels of activated H-Ras. The importance of R-Ras/H-Ras balance in regulating monocyte binding was shown by overexpression studies. Constitutively active R-Ras enhanced monocyte adhesion, whereas coexpression with constitutively active H-Ras was inhibitory. Elevated cAMP, mediated by OxPAPC and specific components POVPC and PEIPC, was responsible for R-Ras activation, and dibutyryl cAMP and pertussis toxin were also effective activators of R-Ras. Using inhibitor and dominant-negative constructs, we demonstrated that phosphatidylinositol 3-kinase (PI3K) was a key downstream effector of R-Ras in this pathway.. OxPAPC, POVPC, and PEIPC induce a cAMP/R-Ras/PI3K signaling pathway that contributes to monocyte/endothelial cell adhesion and potentially atherosclerosis.

Topics: Animals; Cattle; Cell Adhesion; Cyclic AMP; Dose-Response Relationship, Drug; Endothelium, Vascular; GTP Phosphohydrolases; Humans; Integrin beta1; Intercellular Signaling Peptides and Proteins; Monocytes; Oxidation-Reduction; Peptides; Phosphatidylcholines; Phospholipid Ethers; Phospholipids; ras Proteins; Signal Transduction