內皮細胞組織因子在心血管疾病的角色

The Role of Endothelial Tissue Factor in Cardiovascular Diseases

王黃舟(Huang-Joe Wang)

指導教授 ： 黄海美

國立清華大學/生命科學院/生物科技研究所/博士(2010年)

https://doi.org/10.6843/NTHU.2010.00657

摘要

Atherosclerosis is a gradual process that starts early in childhood. It may clinically manifest as coronary artery disease, ischemic stroke, and peripheral arterial occlusive disease. In the later stages of life, atherothrombosis, which is defined as an atherosclerotic plaque disruption with superimposed thrombosis, is the leading cause of morbidity and mortality in the developed countries. The magnitude of the thrombotic processes triggered upon plaque disruptions, is dependent upon tissue factor (TF). TF is the principal initiator of thrombus formation of extrinsic coagulation system. Previous reports have documented that thrombin could elicit TF production in endothelial cells coming from human umbilical cord vein and human saphenous vein. We demonstrate that endothelial cells from arterial side (i.e human aortic endothelial cells, HAECs) still preserve the same response to human thrombin regarding to its ability to induce TF expression.
Patients with diabetes mellitus have increased cardiovascular morbidity and mortality. Diabetes is associated with a hypercoagulable state. In addition, TF antigen is elevated in diabetic patients with microvascular complications and TF activity is reduced in diabetic patients with improved glycemic control. Hyperglycemia is a major contributor to the vascular diseases associated with diabetes. The hyperglycemia-induced formation of reactive oxygen species can lead to endothelial dysfunction and promote the formation of atherosclerotic plaques. However, we demonstrate that high glucose conditions do not provide the sufficient stress required to induce TF expression in HAECs.
Percutaneous intervention using coronary metallic stents has been commonly used in the treatment of atherothrombotic lesions in the coronary arteries since the mid-1990s. However, angiographic in-stent restenosis still occurs in 20–30% of the patients. In order to prevent in-stent restenosis, drug-eluting stents (DESs) capable of providing prolonged local delivery of antiproliferative agents were developed in the early 2000s. One of the first-generation DESs was paclitaxel-eluting stents (PESs). Paclitaxel is a microtubule-stabilizing drug that disrupts the cell cycle in the G2/M phase. It is used in DESs because of its ability to reduce in-stent restenosis by inhibiting vascular smooth-muscle cell proliferation and migration. Patients with PESs are concerned with stent thrombosis caused by premature discontinuation of dual antiplatelet therapy or clopidogrel resistance. We demonstrate that paclitaxel alone can up-regulate endothelial TF expression, which can explain PES-associated thrombotic risks.
Some naturally occurring substances in a normal diet provide a new insight in cardiovascular therapy. Green tea, particularly its major polyphenolic constituent, (-)-epigallocatechin-3-gallate (EGCG), possesses remarkable cancer therapeutic potential as well as cardioprotective effects. The beneficial cardiovascular effects of EGCG may be the result of its pleiotropic effects, which include its antioxidant, antithrombogenic, and anti-inflammatory effects We demonstrate that EGCG can inhibit TF expression in thrombin/paclitaxel- stimulated endothelial cells via the inhibition of JNK phosphorylation. The unique property of EGCG may be used to develop a new drug-eluting stent by co-coating EGCG and paclitaxel.

關鍵字

人類主動脈內皮細胞 ； 凝血酶 ； 組織因子 ； 糖尿病 ； 葡萄糖 ； 藥物塗層支架 ； 支架栓塞 ； 太平洋紫杉醇 ； 益多酚

並列摘要

動脈硬化是一種從小時候就緩慢產生的過程，臨床上它可表現為冠狀動脈疾病、缺血性腦中風、和周邊動脈阻塞疾病。在人晚年時，動脈硬化斑塊可能會破損，造成血液中產生血栓覆蓋在這些破損的動脈硬化斑塊上，進而造成動脈硬化栓塞症。而這正是造成許多已開發國家的主要疾病和死亡的原因。動脈硬化斑塊破損時所刺激血栓產生的強度與組織因子有密切的相關。組織因子是外源性凝血系統產生血栓的主要起始者。過去的研究已經證實凝血酶可以誘發人類的臍帶靜脈內皮細胞和人類的隱靜脈內皮細胞組織因子的產生。我們的研究顯示，凝血酶針對人類動脈端(主動脈內皮細胞)內皮細胞一樣保有誘發組織因子產生的能力。
糖尿病患者其心血管的疾病和死亡都會增加。糖尿病患血液有較易凝結的特性。此外，組織因子的抗原在有微細血管併發症的糖尿病患者血中也會增加， 而血中組織因子的活性在糖尿病患者獲得良好血糖控制時也會下降。高血糖是造成糖尿病患者血管疾病的一個主要原因，高血糖所誘發的反應性氧族會造成內皮功能失常和促進動脈硬化斑塊的產生。但是，我們的研究顯示，以高葡萄糖去刺激人類主動脈內皮細胞並無法提供足夠的刺激誘發組織因子的產生。
經皮去做冠狀動脈血管成形術中，使用冠狀動脈的金屬支架以治療動脈硬化班塊栓塞症在1990年代中期後就非常普遍。但是，冠狀動脈血管攝影中顯示支架內再狹窄的比例仍高達 20-30%。為了要減少支架內再狹窄，可以提供長期局部的抗增生物質釋放的藥物塗層支架在2000年代初期被研發出來。第一代的藥物塗層支架上，有一種是以太平洋紫杉醇塗層的藥物支架。太平洋紫杉醇是一種會穩定微管，進而干擾細胞G2/M週期的藥物。它因為能抑制血管平滑肌細胞的增生和移行，進而減少支架內再狹窄，而被使用在藥物塗層支架。接受太平洋紫杉醇塗層支架的病患，若太早將雙重抗血小板藥劑停掉，或是有保栓通抗性的患者，有可能產生支架栓塞。我們的研究顯示，太平洋紫杉醇本身能使內皮細胞組織因子增加，這發現可以幫助我們去解釋太平洋紫杉醇塗層支架所相關的栓塞風險。
在正常飲食中的某些自然的物質對心血管疾病治療提供一個新的視野。綠茶裏面所含有主要多酚類成份益多酚具有極佳的癌症治療的潛能與心血管保護效果。益多酚的心血管保護效果可能是因為它具有抗氧化、抗栓塞、抗發炎等多效性有關。我們的研究顯示，益多酚可以抑制凝血酶和太平洋紫杉醇刺激下內皮細胞組織因子的產生，而這抑制主要是透過c-Jun-終端激酶的磷酸化的抑制。這個益多酚特有的特性可能可以利用來發展新的有益多酚和太平洋紫杉醇共同塗層的藥物支架。

並列關鍵字

Human aortic endothelial cell ； Thrombin ； Tissue factor ； Diabetes mellitus ； Glucose ； Drug-eluting stent ； Stent thrombosis ； Paclitaxel ； (-)-Epigallocatechin-3-gallate

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