Abstract 14320: Anti-Phosphorylcholine IgG Antibodies Reduce Restenosis and Vascular Inflammation by Inhibition of the Unfolded Protein Response in a Mouse Model of Accelerated Atherosclerosis
Background Restenosis due to inflammatory vascular remodeling remains a major issue in PCI. Anti-phosphorylcholine antibodies (anti-PC) are inversely related to CVD risk and natural IgM anti-PC prevent oxLDL uptake by macrophages, inflammation and atherogenesis. Unlike IgM, IgG abs can be produced in large quantities, allowing clinical application. Unfolded protein response (UPR), a set of signaling pathways activated during stress, is now emerging as an important link between inflammation and atherosclerosis.
Hypothesis Anti-PC inhibit accelerated atherosclerosis by modulating the UPR in vascular cells.
Methods and Results Polyclonal IgM and IgG anti-PC abs from human serum and a recombinant anti-PC IgG construct, containing the murine T15/E06 PC antibody variable region and a human IgG1 constant region, were used to study oxLDL-uptake by THP-1-derived macrophages. Only IgM anti-PC, but not polyclonal or recombinant IgG anti-PC inhibited this process. However, both IgM and IgG anti-PC could prevent in vitro UPR activation, induced in endothelial cells by group X PLA2-phospholipolized LDL, as measured by UPR gene expression. Recombinant T15/E06 abs were used to passively immunize ApoE*3Leiden mice on a Western-type diet undergoing femoral arterial cuff placement to induce restenosis. T15/E06 significantly reduced early macrophage and leukocyte infiltration in the arterial wall and intimal thickening by >70% (p<0.001) after 14d, accompanied by increased relative SMC medial wall area and reduced relative leukocyte and macrophage areas in the arterial wall. Expression of UPR markers BiP/GrP78 and CHOP in the arteries was reduced by T15/E06 treatment.
Conclusions We showed that recombinant anti-PC IgG reduced accelerated atherosclerosis in mice potentially through UPR inhibition. Human IgG anti-PC has therefore potential as a new treatment of inflammation-associated CVD.
- © 2010 by American Heart Association, Inc.