on June 12, 2003
Published online before print June 12, 2003, doi: 10.1161/01.ATV.0000081215.45714.71
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Submitted on April 28, 2003
Accepted on May 28, 2003
Oxidized Phospholipid-Induced Endothelial Cell/Monocyte Interaction Is Mediated by a cAMP-Dependent R-Ras/PI3-Kinase Pathway
Amy L. Cole ;
From the Departments of Medicine and Pathology (J.A.B.), David Geffen School of Medicine at University of California Los Angeles, Los Angeles, Calif.
* To whom correspondence should be addressed. E-mail: jberliner{at}mednet.ucla.edu.
Objective--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 
5
1 integrin. The present studies identify important signal transduction components regulating this pathway.
Methods and Results--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.
Conclusions--OxPAPC, POVPC, and PEIPC induce a cAMP/R-Ras/PI3K signaling pathway that contributes to monocyte/endothelial cell adhesion and potentially atherosclerosis.
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