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1 Pathology, UCDavis Medical Center, Sacramento, California, United States
* To whom correspondence should be addressed. E-mail: ijialal{at}ucdavis.edu.
Monocyte-endothelial cell adhesion is a key early event in atherogenesis. CRP, a cardiovascular risk marker is known to stimulate intercellular and vascular cell adhesion molecules (ICAM, VCAM) in human aortic endothelial cells (HAEC) and induces monocyte-endothelial cell adhesion. In this study, we examined the mechanisms by which native CRP promotes monocyte-endothelial cell adhesion under static conditions and tested the effect of CRP on adhesion under shear flow. Incubation of HAEC with CRP (>25ug/mL) upregulated NFKb activity and this resulted in a significant increase in ICAM (54% increase, p<0.001), VCAM (41% increase, p<0.01) and monocyte-endothelial cell adhesion (44% increase, p<0.02) compared to control. Pre-incubation with antibodies to CD32 and CD64 but not CD16 effectively inhibited this activation. Blocking NFKb activity with inhibitors or a dominant negative Ikappa B significantly decreased ICAM, VCAM upregulation and subsequent monocyte-endothelial cell adhesion. Pre-incubation with antibodies to CD32 and CD64 or transient transfection with siRNA to CD32 attenuated CRP-induced NFkb activity, ICAM, VCAM and monocyte-endothelial cell adhesion under static conditions. Also, the Syk kinase inhibitor Piceatannol and MG132, a proteasome degradation inhibitor produced similar attenuation in NFKb activity, ICAM, VCAM and adhesion. Furthermore, CRP activated endothelial cells supported monocyte rolling, arrest and transmigration in shear flow (2 dynes/cm2) and this was also inhibited by pre-incubation with antibodies to CD32 and CD64. Thus, in HAEC, CRP upregulates monocyte-endothelial adhesion by activation of NFKb through engaging the Fc gamma receptors, CD32 and CD64.
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