Abstract 633: Deficiency of Macrophage 23-kDa Stress Protein Enhances Atherosclerosis via Cholesterol Ester Hydrolysis Dysfunction

Background: Atherosclerosis is characterized by accumulation of modified lipoproteins in intima of aorta leads to the infiltration of monocytes/macrophages. In the atherosclerotic plaque, these macrophages uptake modified lipoproteins and become foam cells. Macrophage 23-kD stress protein (MSP23), a stress-inducible protein, was found for the first time in the macrophages. Recent reports suggested that the shear stress induce MSP23 expression in endothelial cells. However, the role of MSP23 in macrophages has not been studied yet. In this study, we aim to elucidate atheroprotective effect of MSP23 in macrophages. Methods and Results: We show that MSP23 is highly expressed in macrophages among atherogenesis related cells. Double deficiency of MSP23/ApoE mice accelerated plaque formation with increased macrophage infiltrations. Biochemical analyses revealed that MSP23/ApoE double deficient mice exhibited a significant increase in total cholesterol in serum when compared to ApoE deficient mice. Macrophages from MSP23/ApoE double deficient mice expressed higher levels of scavenger receptors and took up more modified lipoproteins compared with ApoE deficient mice, but they expressed low levels of ATP binding cassette protein family A member 1 and were defective in cholesterol efflux. Furthermore, we found that macrophage CE mass was increased in MSP23 deficient macrophages. In bone marrow transplantation experiments, we confirmed that MSP23 plays pivotal atheorprotecitve role in macrophage lineage cells. Conclusions: In this study, we elucidate that MSP23 inhibits atherogenesis by intestinal cholesterol ester hydrolysis and augmenting cholesterol efflux from macrophages resulting in reducing formation of foam cells. Thus, MSP23 appears to be a promising therapeutic target for enhancing cholesterol efflux.