| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 97 === Atherosclerosis, the most common cause of death in most developed countries, is a chronic inflammatory disease caused by interactions between modified lipoproteins, macrophages, T cells, and cellular element with the arterial wall. During atherogenesis, accumulation of oxidized LDL (oxLDL) in the intima and internalization by macrophages leads to formation of foam cell. This process is thought to be the important step during atherogenesis. In macrophages, scavenger receptors (SRs), such as scavenger receptor class A (SR-A) and CD36 are the principal receptors responsible for the binding and uptake of modified LDL. Besides, revers cholesterol transporters (RCTs) such as ATP-binding cassette transporter A1 (ABCA1), ABCG1 and SR-BI play the major role in promoting efflux of free cholesterol from macrophage-foam cells to HDL. Therefore, new approaches of regulating these transporters to inhibit lipid accumulation in macrophage foam cells may be of therapeutic value in preventing atherosclerosis. Recently, animal studies show that curcumin is able to decrease development of atherosclerosis. Curcumin is a component of turmeric, the yellow spice derived from the roots (rhizomes) of the plant Curcuma longa. It has been demonstrated that curcumin possesses wide-ranging anti-inflammatory, antioxidant and other properties to have a significant potential in the treatment of multiple diseases. But the underlying mechanism of the
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effect of curcumin on atherosclerosis is still unclear. The objective of this study was to investigate whether curcumin can prevent foam cell formation and regulate the expressions of SRs and RCTs. In this study, we found that curcumin could increase protein level of ABCA1 and decrease protein level of SR-A by western blotting analysis, while having no effect on ABCG1, CD36 and SR-BI in J774 cell, a mouse macrophage cell line. It also appeared that curcumin had no effect on mRNA level of SR-A and increased mRNA level of ABCA1 through RT-PCR analysis. Furthermore, curcumin can increase the protein degradation rate of SR-A and decrease the protein degradation rate of ABCA1 pretreat with cycloheximide. Moreover, the data showed that the degradation of SR-A by curcumin is mediated via proteasome pathway. By using specific kinase inhibitors, the curcumin mediated SR-A expression was rescued. Iit revealed that PKA (protein kinase A), ERK (extracellular signal-regulated kinase) and JNK (c-Jun N-terminal kinase) were involved in curcumin-mediated SR-A degradation. From the in vivo study, only the expression of SR-A was decreased and the expressions of RCTs were all increased. In summary, our findings suggest that curcumin inhibits formation of foam cell by regulating the expression of SR-A and ABCA1 and explain the effect of curcumin on atherosclerosis.
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