동맥경화 초기 단계 염증에서 산화된 LDL 콜레스테롤의 역할

Dept. of Medical Science/박사Atherosclerosis is a chronic inflammatory disease of the arterial wall. Many studies have shown that retention of low-density lipoprotein (LDL) and recruitment of monocytes into subendothelial space are critical early events in atherosclerotic development. Accumulated LDL in the arterial wall is undergone oxidative modification according to a variety of oxidizing agents and the exposure duration. For these reasons, LDL with different degrees of oxidation exist in the atherosclerotic plaque. However, there is no report regarding the degree of LDL oxidation and macrophage differentiation. Therefore, the specific goal of the Part I study is to know the effects of degree of LDL oxidation on macrophage differentiation and polarization. Based on the level of lipid peroxidation, LDL is classified into high-oxidized LDL (high-oxLDL) and low-oxidized LDL (low-oxLDL). The differentiation profiles of macrophages were determined by surface receptor expression and cytokine secretion profiles in THP-1 cells and primary human monocytes. As a result, low-oxLDL induces macrophage polarization towards M1-like phenotype whereas high-oxLDL induces M2-like phenotype. Therefore, these results suggest that the degree of LDL oxidation influences the differentiation of monocytes into M1 or M2 macrophages and determines the inflammatory fate in early stages of atherosclerosis. The Part II of my study focuses on neutrophils. Neutrophils are the first line of the defense against invading pathogens. Neutrophil extracellular traps (NETs) are most recently defined host defense mechanism to eliminate extracellular pathogens. Also, NETs have been implicated in chronic inflammatory diseases such as atherosclerosis. Recent studies have shown that NET components can be found in lesions associated with atherosclerosis. However, the role of NETs in early atherosclerosis is not identified clearly. Therefore, the effects of NETs during early atherosclerosis were tested in the Part II study using ApoE-/- mice and human neutrophils. NETs were detected in ApoE-/- mice in early stage of atherosclerosis and circulating oxLDL induces NET formation. Especially, NETs induced by oxLDL promote endothelial dysfunction via MMP-9. Collectively, our results suggest that oxLDL-induced NET formation affects endothelial cells in early atherosclerosis and promotes LDL deposition into the intima. Taken together with the results from the Part I and Part II, I suggest that the circulating oxLDL as well as intimal oxLDL play crucial roles for development of early atherosclerosis.ope