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研究生:黃御筑
研究生(外文):Yu-Chu Huang
論文名稱:薑黃素預防泡沫細胞之形成是經由降低A型清除接受體的蛋白表現及提升三腺甘酸結合性傳輸蛋白A1的蛋白表現
論文名稱(外文):Curcumin prevents foam cell formation through down-regulation of scavenger receptor A and up-regulation of ATP-binding cassette transporter A1
指導教授:李宗玄吳鈺琳
指導教授(外文):Tzong-Shyuan LeeYuh-Lin Wu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:77
中文關鍵詞:薑黃素動脈硬化泡沫細胞三腺甘酸結合性傳輸蛋白A1A型清除接受體
外文關鍵詞:curcuminatherosclerosisfoam cellATP-binding cassette transporter A1scavenger receptor class A
相關次數:
  • 被引用被引用:2
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  • 下載下載:62
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動脈粥狀硬化是已開發國家中,主要罹病及致死的主因之一。動脈粥狀硬化是一種由被修飾的低密度脂蛋白(modified low-density lipoprotein, modified LDL)、巨噬細胞(macrophage)、T細胞和血管壁的細胞分子互相作用形成的慢性發炎疾病,在粥狀動脈硬化發展的過程(atherogenesis)中,巨噬細胞會吞食大量堆積在血管壁內膜(intima)中的氧化修飾低密度脂蛋白(oxLDL)而形成泡沫細胞(foam cell),此過程被視為是形成動脈粥狀硬化的關鍵過程;而在巨噬細胞表面會表現清除接受體(scavenger receptors, SRs)像是A型清除接受體(SR-A)和CD36負責與氧化修飾低密度脂蛋白結合並且吞噬;除此之外,膽固醇逆轉運輸體(reverse cholesterol transporters, RCTs)例如三腺甘酸結合性傳輸蛋白A1(ATP-binding cassette transporter A1, ABCA1)和三腺甘酸結合性傳輸蛋白G1(ABCG1)以及B1型清除接受體(SR-B1)等蛋白可以將膽固醇運輸至胞外,因此若能針對調節這些脂質運輸蛋白的表現而達到抑制脂質在巨噬細胞內的堆積和泡沫細胞的形成,或許可以成為預防動脈粥狀硬化疾病的一個著眼點。近年來經動物實驗發現薑黃素(curcumin)可以有效的降低動脈粥狀硬化的發展,薑黃素是從香料植物薑黃(Curcuma longa)的根莖部所萃取出的化合物,在過去的研究已經指出,薑黃素具有抗發炎、抗氧化、抗癌等作用,並且深具潛力開發成多種慢性發炎疾病的治療藥物;然而,目前我們對於薑黃素可以減緩動脈粥狀硬化其中的機制仍然不甚清楚,因此,本實驗目的即為研究薑黃素是否可以防止泡沫細胞形成及調節SRs
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或RCTs的表現。我們採用小鼠巨噬細胞株J774細胞作為本實驗的實驗模式,利用西方墨點法觀察,可以發現薑黃素會造成J774細胞的ABCA1蛋白表現量增加以及SR-A蛋白表現量減少,但對於ABCG1、SR-BI和CD36的表現量則沒有影響;以反轉錄聚合酶連鎖反應技術檢測,則顯示薑黃素不會改變SR-A的訊息核醣核酸表現量但會使ABCA1的訊息核醣核酸表現量增加;此外,在蛋白質合成抑制劑(cycloheximide)的前處理下,薑黃素可以增加SR-A蛋白分解的速度並且減緩ABCA1蛋白分解的速度;若給予細胞前處理蛋白酶體抑制劑(MG132)會防止薑黃素所引起的SR-A蛋白分解,但若給予細胞前處理溶小體抑制劑(chloroquine),則無此效果。我們更進一步發現,若分別以特定的激酶抑制劑預處理細胞,可以發現SR-A蛋白分解的現象會被抑制,其顯示A型蛋白激酶(protein kinase A, PKA)、細胞外信號調節激酶 (extracellular signal-regulated kinase, ERK)以及c-Jun氨基末端激酶(c-Jun N-terminal Kinase, JNK)參予在其中。由動物實驗觀察,薑黃素可以降低SR-A蛋白的表現量但提升所有RCT的蛋白表現。由本研究得知,薑黃素會降低泡沫細胞的形成,其中會加速SR-A蛋白分解,並且;另一方面,薑黃素會促使ABCA1蛋白表現增加。
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
VI
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.
Table of contents
致謝..............................................................................................................................IV
Abstract.......................................................................................................................V
摘要............................................................................................................................VII
Introduction..................................................................................................................1
Atherosclerosis.............................................................................................................1
Atherogenesis........................................................................................................1
Macrophage-derived foam cells..........................................................................3
Foam cell formation.............................................................................................4
Influx of cholesterol.............................................................................................5
Efflux of cholesterol.............................................................................................8
Curcumin....................................................................................................................11
Biological activity of curcumin.........................................................................12
Curcumin and atherosclerosis..........................................................................14
Objective.....................................................................................................................14
Materials and Methods..............................................................................................16
Materials.............................................................................................................16
Cell culture.........................................................................................................16
Oil red O staining...............................................................................................16
II
Preparation of whole cell lysates......................................................................17
Western blot analysis.........................................................................................17
Total RNA isolation............................................................................................18
Reverse transcription (RT)...............................................................................18
Polymerase chain reaction (PCR).....................................................................19
Animal experiments...........................................................................................20
Statistical analysis..............................................................................................20
Results........................................................................................................................22
Curcumin attenuates lipid accumulation in murine macrophages.......................22
Curcumin reduces protein expression of SR-A but not CD36 in murine macrophages.......................................................................................................22
Curcumin increases protein expression of ABCA1 but not ABCG1 andSR-B1 in murine macrophages...................................................................22
Curcumin has no effect on mRNA level of SR-A in murine macrophages...23
Curcumin downregulates protein level of SR-A time-dependently in murine macrophages.......................................................................................................23
Curcumin increases the degradation rate of SR-A protein in murine macrophages.......................................................................................................23
Curcumin-mediated SR-A degradation is via proteasome pathway in murine
III
macrophages.......................................................................................................24
The downregulation of SR-A by curcumin is mediated through PKA, ERK and JNK in murine macrophages.....................................................................25
Curcumin time-dependently upregulates mRNA expression of ABCA1 in murine macrophages.........................................................................................25
Curcumin time-dependently upregulates protein expression of ABCA1 in murine macrophages.........................................................................................25
Curcumin attenuates the degradation rate of ABCA1 protein in murine macrophages.......................................................................................................26
Curcumin reduces protein expression of SR-A but not CD36 in vivo...........26
Curcumin increases protein expression of ABCA1, ABCG1 and SR-B1 in vivo.......................................................................................................................26
Discussion....................................................................................................................28
References...................................................................................................................35
Figures........................................................................................................................55
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