|NAGARAJAN, SHANMUGAM - ACNC/UAMS
Submitted to: American Heart Association Meeting
Publication Type: Proceedings
Publication Acceptance Date: 10/15/2005
Publication Date: 11/12/2005
Citation: Nagarajan, S. 2005. Role of iggfcgamma receptor in the progression of atherosclerosis. American Heart Association "Learn and Live" Research Symposium, November 12, 2005, Dallas, Texas. p. 27.
Interpretive Summary: Higher levels of bad cholesterol (LDL) cause thickening of blood vessels. This process is known as atherosclerosis. LDL is modified to form oxidized form of LDL. Our immune system raises antibody response against oxidized form of LDL. In this study, we tested the effect of antibodies in the progression of atherosclerosis. Our findings show that antibody response increases blood cells to stick to the blood vessels. This process is controlled by one of the proteins on the blood cells. In future studies, we will explore if early exposure to dietary factors can block the autoantibody generation.
Technical Abstract: Immune responses against oxidized-LDL (oxLDL) have been demonstrated in both animal models and clinical studies. However, the role of anti-oxLDL antibody in the progression of atherogenesis is not well understood. Since monocytes express IgG-Fcgamma receptors (Fc[gamma]R) that bind to immune complexes, we hypothesize that generation of oxLDL-IC in atherosclerotic conditions may enhance monocyte adhesion to endothelium. To address this hypothesis, we carried out a ligand (oxLDL-IC)-coated plate adhesion assay. Human monocytic cell lines U937 and monomac adhered to oxLDL-IC coated plates. Clinically, anti-oxLDL IgG titer may influence the formation of oxLDL-IC, and subsequent monocyte adhesion. Further, monocytes express CD36 and CD32 (one of the Fc[gamma]R), receptors for oxLDL and oxLDL-IC, respectively. Therefore to determine the relative contribution of CD36 and CD32 in the oxLDL-IC mediated monocyte adhesion, assays were repeated using oxLDL-IC prepared with different concentrations of anti-oxLDL IgG. U937 cells showed saturation adhesion kinetics after a 20% decrease in adhesion at the lowest concentration of anti-oxLDL IgG, while monomac cells showed a dose-dependent increase in the adhesion. To validate the findings from monocytic cell lines, peripheral blood monocytes from normal donors were used, and similar adhesion to oxLDL-IC was observed. To further confirm our findings with ligand-mediated monocyte adhesion, an endothelial cell adhesion assay was developed using oxLDL-IC-coated endothelial cells. Both monomac and U937 adhered to endothelial cells coated with oxLDL-IC. In all the adhesion assays, addition of anti-CD32 mAb inhibited monocyte adhesion completely. In conclusion, the findings from this study suggest that, when a strong antibody response occurs against ox-LDL, Fc[gamma]R could play a vital role in promoting monocyte adhesion, a key event in the initiation and the progression of atherogenesis.