Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23278
標題: 小蘗鹼抑制血小板衍生生長因子誘導大白鼠動脈血管平滑肌細胞增生及轉移之分子作用機轉
The molecular mechanisms of berberine-mediated inhibitory effect on platelet-derived growth factor-induced proliferation and migration in rat aortic smooth muscle cells
作者: 尹修竹
Yin, Sui-Chu
關鍵字: Berberine;小蘗鹼;Atherosclerosis;Restenosis;Rat vascular smooth muscle cells(RASMCs);Platelet-derived growth factor-BB (PDGF-BB);Proliferation;Migration;動脈粥樣硬化;血管再狹窄;血管平滑肌細胞;血小板衍生生長因子;細胞增生;細胞轉移
出版社: 生命科學院碩士在職專班
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摘要: 
中文摘要

血管平滑肌細胞(vascular smooth muscle cells, VSMCs)的異常增生(proliferation)及轉移(migration)會造成血管內膜(intima)增厚,是導致心血管疾病如動脈粥樣硬化(atherosclerosis)、靜脈移植栓塞(vein graft occlusion)和經皮冠狀動脈腔內血管造形術(percutaneous transluminal coronary angioplasty, PTCA)之後血管再狹窄(restenosis)發生的關鍵原因。在臨床上,這些疾病僅能藉由藥物控制或外科手術來進行治療,但往往在數月或數年之後,患者又會再度復發,到目前為止仍無法有效治療,因此尋找新的治療藥物及治療方法為當務之急。當血管內膜受到損傷時,血管內皮細胞、血管平滑肌細胞、血小板及巨嗜細胞均會分泌大量的生長因子如血小板衍生生長因子(platelet-derived growth factor, PDGF)、纖維母細胞生長因子(basic fibroblast growth factor, bFGF)、類胰島素生長因子(insulin-like growth factor, IGF)和血管收縮素(angiotensin Ⅱ, Ang Ⅱ)等等,來誘導血管平滑肌細胞的增生及轉移,進而造成新生血管內膜(neointima)增厚及血管再狹窄。小蘗鹼(berberine)是中草藥黃連(Coptis chinensis)的主成分之一,屬於異喹啉類(isoquinoline)植物性生物鹼,具有降膽固醇、降血壓、降血糖、抑制細胞增生、抗癌、消炎解毒、抗菌、殺蟲等等功效。文獻上曾報導小檗鹼具有抑制血管平滑肌細胞增生及轉移的作用,但其確切的調控機轉則仍未有定論。在我們之前的研究中曾經證實體外培養的血管平滑肌細胞受到機械性損傷後,會釋出大量的PDGF並且促進細胞的增生,而此現象會受到小蘗鹼所抑制。本研究因此直接以PDGF-BB誘導體外培養的血管平滑肌細胞之增生及轉移,進而探討小蘗鹼抑制此現象的作用機轉。結果發現,小蘗鹼可透過將細胞週期停滯在G0-G1期而無法進入S期來抑制PDGF-BB所誘導血管平滑肌細胞的增生。經由顯微鏡下觀察及細胞計數的結果發現,小檗鹼確實可以3、10、30及100 uM濃度相關性地抑制PDGF-BB所誘導血管平滑肌細胞的增生。透過西方墨點轉漬分析(Western blotting assay)證實在此過程中,PDGF-BB活化了MEK1/2(mitogen-activated protein kinase 1/2)、ERK1/2(extracellular signal-regulated kinase 1/2)、Akt,並且增加Cyclin-D1、-D3的表現量及Cdk (cyclin dependent kinase)2、4的活性;藉由半定量RT-PCR分析(semi-quantitative reverse-transcription PCR assay)證實PDGF-BB在核酸層次對血管平滑肌細胞即具有調控作用。而小蘗鹼則顯著地抑制PDGF-BB所誘導MEK1/2、ERK1/2、Akt的活化及Cyclin-D1、-D3、Cdk2、4的表現量,並增加Cdk inhibitor p21CIP1/WAF1的表現量。Cdk inhibitor p21CIP1/WAF1的表現量增加可能是由於小蘗鹼活化AMP-activated protein kinase(adenosine monophosphate-activated protein kinase, AMPK)造成p53的磷酸化所致。Wound healing assay與Boyden chamber assay證實小蘗鹼可阻止PDGF-BB所誘導血管平滑肌細胞的轉移。進一步透過分析發現PDGF-BB增加Ras、Rac1、Cdc42的活性,同時此活性也受到小蘗鹼所抑制。由實驗結果得知小蘗鹼阻斷PDGF-BB所活化Ras/MEK/ERK-Akt路徑來抑制血管平滑肌細胞的增生;阻斷PDGF-BB所活化Rac/Cdc42路徑來抑制血管平滑肌細胞的轉移。因此,藉由中草藥小蘗鹼抑制血管平滑肌細胞的增生及轉移的特性,將有助於未來開發新藥來預防及治療心血管疾病。

Abstract

Deregulated proliferation and migration of vascular smooth muscle cells (VSMCs)induced neointima formation plays an important role in many coronary diseases including the pathogenesis of atherosclerosis, vein graft occlusion and post-angioplasty restenosis. Clinically up to date, there were still no effective therapy to cure such vascular diseases. Therefore, it is very imperative to find new drugs and strategies to treat such diseases. Platelet-derived growth factor (PDGF) is released from VSMCs, vascular endothelial cells (VECs), platelets or macrophages after percutaneous coronary intervention and is strongly associated with neointima formation and restenosis. Berberine, an isoquinolinal plant alkaloid isolated from a well-known Chinese medicinal herb Huanglian (Coptis chinensis), has cholesterol-lowering, hypotensive, cell-growth inhibition, anti-cancer, anti-inflammatory and anti-microbial effects. Berberine could inhibit VSMCs proliferation and migration, yet the exact mechanisms are still unknown. Our previous results showed that berberine is capable of inhibiting cell growth and endogenous PDGF synthesis in rat aortic vascular smooth muscle cells(RASMCs)after in vitro mechanical injury. In the preceeding study, we explore the effects of berberine on RASMCs growth, migration, and downstream signaling events after exogenous PDGF-BB stimulation in vitro in order to mimic a post-angioplasty PDGF shedding condition. By flow cytometry analysis, our results showed that berberine could dose-dependently inhibit PDGF-BB-induced proliferation and cause cell cycle arrest at G0-G1 phase. Western blot analysis showed that PDGF-BB stimulated the activation of MEK1/2 (mitogen-activated protein kinase 1/2), ERK1/2 (extracellular signal-regulated kinase 1/2), Akt, and increased the expression of Cyclin-D1, -D3 and Cdk (cyclin dependent kinase)2, 4, and down-regulated Cdk inhibitor p21CIP1/WAF1expression. Semi-quantitative reverse-transcription PCR (RT-PCR) assay further confirmed the increase in cyclin-D1, -D3 and CDK2, 4 expression at transcriptional level. Berberine increased the activity of AMPK (adenosine monophosphate-activated protein kinase, AMP-activated protein kinase), which led to phosphorylation activation of p53 and up-regulated protein level of Cdk inhibitor p21CIP1/WAF1. Berberine significantly suppressed MEK 1/2, ERK1/2, Akt activation and cyclin-D1, -D3 and Cdk2, 4 expression after PDGF-BB stimulation. Moreover, wound healing assay and Boyden chamber assay showed that berberine prevented PDGF-BB-induced migration in RASMCs. Furthermore, from pull-down assay demonstrated stimulation of RASMCs with PDGF-BB led to a transient increase in Ras, Rac1, Cdc42 activities; however, pretreatment with berberine for 24 h significantly inhibited PDGF-BB-induced Ras, Rac1, Cdc42 activation. These data suggest that berberine inhibited PDGF-BB-induced RASMCs growth via activating the AMPK/p53/p21CIP1/WAF1 signaling, inactivating the Ras/MEK/ ERK- Akt pathway, and suppress PDGF-BB-stimulated migration via inhibition of Rac/Cdc42. These observations offer a molecular explanation for the anti-proliferative and anti-migratory properties of berberine, and suggest that this drug may potentially be used in treating disorders due to unproperly SMCs proliferation.
URI: http://hdl.handle.net/11455/23278
其他識別: U0005-1408200710091600
Appears in Collections:生命科學系所

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