臺灣博碩士論文加值系統

Caveolin-1 (Cav-1) 為構成Caveolae的重要蛋白，負責調控許多訊息傳遞路徑，且在血管平滑肌細胞中高度表現。動脈粥狀硬化(Atherosclerosis) 為心血管中主要的疾病之一，在大部分的心血管疾病病程中，都可以發現內膜增厚( Intima hyperplasia)的現象，而造成這種現象的最主要因素為血管平滑肌細胞的增生與遷移。先前的研究指出，與正常血管平滑肌細胞比較，Cav-1缺失小鼠的血管平滑肌細胞具有不正常的高增生率、高遷移能力。過去Cav-1與細胞增生的機制已被一一發現，但是Cav-1與細胞遷移的關係卻仍然不清楚。Pyrogallol是一種從香椿中萃取的多酚類，多酚類一直被認為具有抗氧化的能力，能保護血管，降低心血管疾病的發生，但是pyrogallol也被證實會製造出大量的自由基。因此本實驗目的在探討Cav-1對血管平滑肌細胞中的遷移中所扮演的角色及此天然化合物是否能抑制血管平滑肌細胞的遷移與相關機制，並利用小鼠頸動脈結紮手術評估此藥物對正常小鼠與Cav-1基因缺陷小鼠內膜增生的影響。利用原子力顯微鏡，可以觀察到Cav-1缺陷小鼠的血管平滑肌細胞其細胞表面含有較多filopodia及較少lamellipodia，且其基質金屬蛋白酶(Matrix metalloproteinase, MMP)家族中的MMP-3、MMP-13與cox-2表現量都明顯的比正常細胞少，而MMP-14的表現量會上升。此外，從細胞遷移分析實驗(Wound healing assay)中亦證實pyrogallol可抑制小鼠血管平滑肌細胞遷移，但是Cav-1的存在會影響其調控的路徑：當Cav-1存在時，pyrogallol是透過抑制MMP-2的活性及提高MMP家族的抑制蛋白(Tissue inhibitor of metalloproteinases, TIMP )的TIMP-1。但在Cav-1缺失後，pyrogallol則透過抑制MMP-1及提高TIMP-2的表現量。此外，在活體實驗中，pyrogallol也可以明顯抑制頸動脈結紮三周的小鼠血管內膜增厚，亦觀察到血清中的ProMMP-9活性在小鼠頸動脈結紮二天內會明顯增加，但二天後到第七天會逐漸降低；MMP-9之活性則是在第二天到第七天都有大量表現，而在分別經過8次腹腔注射doxyxyxline及pyrogallol的組別，其血清中MMP-2與MMP-9活性都沒有明顯的變化。本實驗結果顯示pyrogallol可有效降低血管平滑肌細胞的遷移及抑制頸動脈血管結紮後的內膜增厚，具有抗動脈粥狀硬化的潛力。

Caveolin-1 (Cav-1) is identified as the major unit forms scaffold structure, regulates several signaling pathway and abundantly expressed in vascular smooth muscle cell (VSMC). VSMC migration contributes to intimal hyperplasia, which is involved in several vascular diseases including atherosclerosis. Previous study demonstrated that Cav-1-deficient VSMC showed an abnormal increase in proliferation and migration rate as compared with wild-type. The mechanism of Cav-1 in VSMC proliferation is already demonstrated, but the role of Cav-1 in VSMC migration has not been certain. In addition, Pyrogallol, a polyphenol compound, plays an antioxidant character and reduces the risk of cardiovascular disease. This study attempted to dissect the role of Cav-1 in VSMC migration and investigate effect of pyrogallol on VSMC mobility and carotid artery ligation to mimic a neointimal hyperplasia phenotype. The data showed that Cav-1 deficient VSMC down-regulated the mRNA expression of MMP-3, MMP-13 and cox-2 whereas up-regulated of MMP-14 expression. Moreover, the AFM picture also showed that Cav-1 deficient VSMC had less lamellipodia and higher filopodia than wild-type VSMC. Additionally, Pyrogallol could significantly inhibit VSMC migration in the presence and absence of Cav-1 via two different pathways. Pyrogallol inhibited WT VSMC migration by repressing MMP-2 activity and increasing TIMP-1 expression. In contrast, without Cav-1 in VSMC, pyrogallol inhibits its migration via promoting the TIMP-2 expression and down-regulating MMP-1 expression. In vivo study, pyrogallol also could significantly inhibit the intima formation at third week after mouse carotid ligation. At the early stage of carotid ligation in mice, the proMMP-9 was significantly increased from Day 0 to Day 2 and decreased from Day 2 to Day 7 at a time-dependent manner from zymography of serum. Furthermore, MMP-9 activity was elevated from Day 2 to Day 7. However there was no significant difference in both MMP-2 and MMP-9 activity after treated with pyrogallol and doxycycline for 8 times, respectively. The present study suggests that pyrogallol could prevent the severity of neointima hyperplasia via a ROS scavenger in mouse carotid ligation model and has potential anti-atherogenic effects in the treatment of vascular diseases.

ABSTRACT III
ABBREVIATIONS VII
INTRODUCTION
The Pathogenesis of Atherosclerosis 1
Role of MMPs in Atherosclerosis 2
Characterization of VSMC in Atherosclerosis 4
Caveolae and Caveoin-1 6
Carotid ligation animal model 7
RATIONALE AND SPECIFIC AIMS 9
RESEARCH DESIGN AND METHODS
Research design - in vitro 11
Research design - in vivo 12
Animal feeding and diets 13
Pyrogallol and doxycycline preparation 13
Carotid ligation model 13
VSMC Isolation and Cell Culture 14
Identification of VSMC 15
Cell viability assay 16
Wound Healing Scratch assay 17
Gelatin Zymography 17
Western blotting 18
Reverse transcription PCR (RT-PCR) 18
Statistical Analyses 19
RESULTS
Identification of isolated vascular smooth muscle cells 21
The morphology of VSMC by AFM scanning 21
Effect of pyrogallol and doxycycline on VSMC viability 21
Effect of pyrogallol and doxycycline on VSMC migration 22
The roles of Cav-1, pyrogallol and doxycycline on VSMC mobility 22
The roles of Cav-1, pyrogallol and doxycycline on MMPs family expression 23
The roles of Cav-1, pyrogallol and doxycycline on cox-2 and TGase 2 expression 24
Effect of pyrogallol and doxycycline on neointima formation: Histopathological changes and morphometric analysis 25
The change of MMP-2 and MMP-9 activity in mice serum during carotid ligation 26
DISCUSSION 27
FUTURE WORKS 35
RESERENCES 37
TABLES 49
FIGURES 52

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