臺灣博碩士論文加值系統

中文摘要
在台灣地區十大死因中，心血管疾病及高血壓性疾病等，皆與動脈粥狀硬化有關。目前用於治療冠狀動脈阻塞疾病的主要方法是經皮穿腔冠狀動脈血管成形術（percutaneous transluminal coronary angioplasty, PTCA），亦即所謂氣球擴張血管成形術；以及置入支架（stent）兩種。但是在手術後半年內，約有30~50％的病人會發生血管再狹窄（restenosis）。過去的研究指出，大麻酚受體可能可做為治療動脈硬化的標地。目前已知大麻主要產生藥理作用的物質為四氫大麻酚（Δ9-tetrahydrocannabinol, Δ9-THC），而其主要的兩個大麻接受器（cannabinoid receptor, CB receptor）為大麻酚第一類接受器（CB1 receptor）與大麻酚第二類接受器（CB2 receptor）。故本研究擬探討當血管內皮細胞損傷後造成的血管再狹窄時，大麻酚系統與平滑肌細胞之間的影響及關係。本研究使用西方墨點法將主要參與血管修復的細胞偵測CB1與CB2 receptor表現量，並觀察平滑肌細胞在加入THC後細胞內MAPK訊號傳遞路徑因子的表現，再以BrdU incorporation assay觀察細胞增生情形。在細胞功能測試方面，使用細胞移行實驗（cell migration assay）觀察加入CB1與CB2 receptor專一性抑制劑後，細胞對THC的生理反應。在動物實驗方面，將小鼠股動脈人為造成血管內皮損傷後，以免疫螢光染色法（Immunofluorescence stain）觀察術後不同時期，血管內皮細胞及平滑肌細胞的CB1與CB2表現量。實驗結果發現，在加入THC後，會造成血管平滑肌細胞內MAPK的表現及促進細胞增生，而分別加入CB1與CB2抑制劑後，可觀察到細胞增生減緩的情形，當同時加入此兩種抑制劑時，更有加乘的效應，顯示THC可能是透過CB1和CB2 receptor促進細胞增生。動物實驗結果顯示，血管內膜損傷後，血管本身的內皮細胞及平滑肌細胞均有更多的CB1與CB2 receptor表現，而自骨髓移轉來的OEC和SPC表現CB1、CB2的量比血管內皮及平滑肌細胞更多。綜合以上實驗結果顯示，在血管再狹窄的形成過程中，THC會促進平滑肌細胞的增生，而加速血管再狹窄的進展，此情形可受到CB1、CB2抑制劑作用，達到抑制細胞增生的效果，進而得到保護效用，避免再狹窄的進行過程。

Abstract
In ten major causes of the death in Taiwan, cardiovascular disease and hypertension are all relate to atherosclerosis. The main methods to treat coronary artery disease are percutaneous transluminal coronary angioplasty, with or without stent implantation. But within the following 6 months after the operation, nearly 30 - 50％ of the patients have coronary restenosis. Previously, reports showed that cannabinoid system might play a role in the treatment of atherosclerosis. Delta-9-tetrahydrocannabinol, or 6a, 7, 8, 10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d ]-pyran-1-ol, is a substance possessing several stereochemical variants. One of them is (2)-trans-delta-9-tetra-hidrocannabinol, also called dronabinol or D9-THC. Two known cannabinoid receptors are namely CB1 and CB2 receptors. In our study, we investigated the effects of THC on the development of intimal hyperplasia on vessels after angioplasty injury. We used western blot to detect CB1 and CB2 receptors, and observed MAPK signal transduction. Cell proliferation capacity were detected by BrdU incorporation assay. In cell functional assays, we used cell migration assay to observe cell migratory ability in response to THC, CB1 antagonist, and CB2 antagonist. In animal experiments, mice underwent femoral artery wire injury. We used immunofluorescence staining to
detect the expression of CB1 and CB2 receptors on injured vessel. Our data demonstrated that in the course of forming atherosclerosis or restenosis, THC probably promoted the proliferation of the vascular smooth muscle cells（SMCs）, and accelerated the progression of restenosis. This effect of THC could be blocked by CB1 and CB2 antagonists, by suppressing SMCs proliferation. Thus, cannabinoids system maybe a valuable target for attenuating the development of intimal hyperplasia, namely restenosis, after vascular injury.

目 錄

中文摘要....................................................................... i
目錄............................................................................... iv
壹、前言......................................................................... 1
一、動脈硬化 (Atherosclerosis) 形成因素及治療........................ 1
二、血管整形術後或置入支架後造成內膜增生 (intimal hyperplasia) 的構成要素................................................

3
三、大麻 (Marijuana) 歷史及作用簡介........................................... 4
四、大麻接受器 (Cannabinoid receptors) 及內生性大麻 (endogenous cannabinoids)..........................................................

6
（一）大麻接受器的發現............................................... 6
（二）合成大麻接受器專一性抑制劑的發展...................... 7
（三）內生性大麻....................................................... 8
五、大麻接受器之訊號傳遞機轉........................................................ 9
（一）G 蛋白耦聯接受器 (G protein couple receptors)........ 9
（二）大麻接受器訊號傳遞機制 (Signal transduction mechanisms of cannabinoid receptors).......................

10
六、Cannabinoid 系統存在於心血管系統........................................ 11
七、Cannabinoid 系統於動脈硬化中扮演之角色............................. 11
八、研究動機........................................................................................ 12
貳、實驗材料與方法..................................................... 13
一、實驗材料...................................................................... 13
（一）實驗細胞.......................................................... 13
（二）實驗動物--Mice.................................................. 13
（三）實驗材料.......................................................... 13
二、實驗方法...................................................................... 16
（一）細胞培養 (Cell culture)........................................ 16
（二）西方墨點分析法 (Western blot)............................. 17
（三）以流式細胞儀偵測細胞增生實驗 (cell proliferation assay).............................................................
21
（四）細胞移行實驗 (cell migration assay)....................... 22
（五）動物實驗 (animal model)...................................... 23
（六）免疫螢光染色法 (Immunofluorescence)................... 24
參、結果......................................................................... 25
一、 造成動脈硬化及血管再狹窄相關細胞CB1與CB2接受器之表現情形................................................................

25
二、 觀察SR141716A (CB1抑制劑)、SR144528 (CB2抑制劑)預先處理人類主動脈平滑肌細胞對於Δ9-THC所造成細胞增生 (proliferation) 之影響........................................



26
三、 觀察SR141716A (CB1抑制劑)、SR144528 (CB2抑制劑)預先處理人類主動脈平滑肌細胞對於Δ9-THC所造成細胞移行 (migration) 之影響........................................................



27
四、觀察Δ9-THC對於人類主動脈平滑肌細胞內MAPK (mitogen-activated protein kinase) 表現的影響.....................

28
五、 觀察CB1與CB2接受器於動物體內血管平滑肌及內皮細胞表現情形................................................................

29
六、 觀察CB1與CB2接受器於動物體內血管內膜進行血管整形術後參與血管再狹窄之平滑肌前驅細胞及內皮前驅細胞表現情形................................................................



30
肆、討論......................................................................... 31
一、 動脈硬化及血管再狹窄相關細胞具有CB1與CB2接受...... 31
二、 Δ9-THC造成人類主動脈平滑肌細胞增生 (proliferation) 之可能機轉.................................................................

33
三、 Δ9-THC並無影響人類主動脈平滑肌細胞的細胞移行 (migration)...............................................................

35
四、 Δ9-THC對於人類主動脈平滑肌細胞內增生傳遞訊息具有強烈的影響.................................................................

36
五、動脈硬化是非常複雜的.................................................. 38
伍、參考文獻................................................................. 39
陸、圖 表....................................................................... 50
Figure 1：觀察人類主動脈平滑肌細胞型態.............................. 50
Figure 2：血管整形術手術情形.............................................. 51
Figure 3：觀察造成動脈硬化及血管再狹窄相關細胞表現CB1及CB2接受器情形....................................................

52
Figure 4：觀察SR141716A(CB1抑制劑)、SR144528(CB2抑制劑)預先處理人類主動脈平滑肌細胞對於Δ9-THC所造成細胞增生 (proliferation) 之影響...............................



54
Figure 5：觀察SR141716A(CB1抑制劑)、SR144528(CB2抑制劑)預先處理人類主動脈平滑肌細胞對於Δ9-THC所造成細胞移行 (migration) 之影響—加藥前......................



55
Figure 6：觀察SR141716A(CB1抑制劑)、SR144528(CB2抑制劑)預先處理人類主動脈平滑肌細胞對於Δ9-THC所造成細胞移行 (migration) 之影響—加藥後24小時...........



56
Figure 7：觀察SR141716A(CB1抑制劑)、SR144528(CB2抑制劑)預先處理人類主動脈平滑肌細胞對於Δ9-THC所造成細胞移行 (migration) 之影響—加藥後48小時...........



57
Figure 8：觀察Δ9-THC對於人類主動脈平滑肌細胞內MAPK 表現的影響.............................................................

58
Figure 9：觀察CB1接受器於動物體內血管平滑肌及內皮細胞表現情形.....................................................................

59
Figure 10：觀察CB2接受器於動物體內血管平滑肌及內皮細胞表現情形..............................................................

60
Figure 11：觀察CB1接受器於動物體內血管內膜進行血管整形術後12天參與血管再狹窄之內皮前驅細胞表現情形.....

61
Figure 12：觀察CB2接受器於動物體內血管內膜進行血管整形術後12天參與血管再狹窄之內皮前驅細胞表現情形.....

62
Figure 13：觀察CB1接受器於動物體內血管內膜進行血管整形術後12天參與血管再狹窄之平滑肌前驅細胞表現情形..

63
Figure 14：觀察CB2接受器於動物體內血管內膜進行血管整形術後12天參與血管再狹窄之平滑肌前驅細胞表現情形..

64
Figure 15：觀察CB1接受器於動物體內血管內膜進行血管整形術後28天參與血管再狹窄之內皮前驅細胞表現情形.....


65
Figure 16：觀察CB2接受器於動物體內血管內膜進行血管整形術後28天參與血管再狹窄之內皮前驅細胞表現情形.....

66
Figure 17：觀察CB1接受器於動物體內血管內膜進行血管整形術後28天參與血管再狹窄之平滑肌前驅細胞表現情形..

67
Figure 18：觀察CB2接受器於動物體內血管內膜進行血管整形術後28天參與血管再狹窄之平滑肌前驅細胞表現情形..

68
柒、附 圖..................................................................... 69
附圖1：大麻應用及研究發展史............................................. 69
附圖2：大麻植物................................................................ 70
附圖3：各種大麻酚類物質及CB1與CB2接受器專一性抑制劑化學結構圖...................................................................................

71
附圖4：CB1與CB2接受器為七個穿膜性蛋白................................ 72
附表1：CB1與CB2接受器相關訊號傳遞路徑................................ 73
附圖5：圖示CB1與CB2接受器主要訊號傳遞路徑....................... 74
附表2：大麻接受器於各種組織表現情形......................................... 75

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