Studies on the mechanism for generation of factors regulating formation and stabilization of plaques in atherosclerosis.

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This study focused to investigate the mechanism for generation of factors implicated in the formation and stabilization of atherosclerotic plaques that induce acute coronary syndrome. In these respects, the mechanism for foam cell formation of macrophages, which is involved in the plaque formation, and for the production of matrix proteins and matrix metalloproteinases (MMP), which are involved in plaque stability, was investigated. The results obtained are as follows.1.Involvement of phospholipase A_2 (PLA_2) in cholesteryl ester formation was revealed in mouse peritoneal macrophages exposed to oxidized low-density lipoproteins (oxLDL). The activation of PLA_2 was evoked by the translocation to membranes in response to oxLDL. Furthermore, the type IVC PLA_2 was shown to play a role for the formation assessed by experiments with type IVA knock down cells, the cells obtained from type IVA knockout mice, and type IVC over expression cells.2.The mechanism for generating MMP-1 when human coronary artery smooth muscle cells were stimulated with oxLDL was investigated. OxLDL was demonstrated to stimulate platelet-derived growth factor receptor followed by activation of extracellular signal-regulate kinase 1/2 and AP-1. Furthermore, in human macrophages obtained by differentiation of human monocytic leukemia cell line, it was characterized that MMP-9 generation induced by oxLDL is regulated by type IVA PLA_2 activation using type IVA PLA_2 knock down cells or the cells from type IVA PLA_2 knockout mice.3.The mechanism for generation of fibronectin that is a component of fibrous caps of plaques was investigated in human mesangial cells stimulated with oxLDL. Reactive oxygen species and activation of SP-1 were associated with the generation. In addition, the generation was suppressed by an inhibitor of type IVA PLA_2 and was not generated in the cells derived from type IVA PLA_2 knockout mice, demonstrating that type IVA PLA_2 contributes to the generation.