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 alpha5beta1 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.
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 alpha5beta1 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.
Authors: Wei Zhong; James R Springstead; Ramea Al-Mubarak; Sangderk Lee; Rongsong Li; Benjamin Emert; Judith A Berliner; Michael E Jung Journal: J Med Chem Date: 2013-10-31 Impact factor: 7.446
Authors: Xinmin Yan; Sangderk Lee; B Gabriel Gugiu; Lukasz Koroniak; Michael E Jung; Judith Berliner; Jinluo Cheng; Rongsong Li Journal: Biochem Biophys Res Commun Date: 2014-01-14 Impact factor: 3.575
Authors: Wendy Tseng; Jinxiu Lu; Gail A Bishop; Andrew D Watson; Andrew P Sage; Linda Demer; Yin Tintut Journal: J Lipid Res Date: 2009-11-11 Impact factor: 5.922