- 學位論文
Statin在血管病變的研究: 1.Atorvastatin在正常血脂的冠心症患者做完介入治療後，對血漿中Adiponectin濃度的影響 2.Simvastatin在高糖狀態下對血管平滑肌細胞增生與位移之影響
Impact of statin on vascular disease:
摘要
冠狀動脈心臟病是糖尿病患者重要的併發症及死因，且糖尿病患者發展出心血管疾病之風險是正常人的二至四倍，故一般認為，罹患糖尿病等同罹患了心血管疾病。現在認為動脈粥狀硬化是一種血管慢性發炎所造成的結果，且血管平滑肌功能的異常會造成糖尿病患者的動脈粥狀硬化及大血管病變。最近adiponectin 被發現有抗發炎，抗糖尿病和抗動脈粥狀硬化的作用。另外，除了降低血脂含量的功能之外，Statins通過刺激一氧化氮（ NO ）合成酶活性以及抗氧化作用而改善血管內皮細胞的功能。它可以強化NO生物活性、 減少血小板粘附、減少血栓形成加強斑塊穩定性和抗發炎作用,因此對經皮冠狀動脈介入治療 (PCI) 的治療效果有促進作用，Statins亦可經由抑制VSMC增生與遷移來降低內膜增殖。因此，statin與adiponectin之間應該存在著某種相關性，但是，statins對血漿adiponectin的作用仍存爭議，且經皮冠狀動脈介入治療對血漿adiponectin濃度的影響亦不清楚。因此我們調查了atorvastatin在正常血脂的冠心症患者做完介入治療後，對其血漿中adiponectin濃度的影響。另外我們也研究了在高葡萄糖、近似糖尿病的情況下，simvastatin抑制血管平滑肌細胞(VSMC)生長之機制。我們的研究證實了atorvastatin在抗發炎和抗動脈粥狀硬化方面的效能，但我們也發現atorvastatin對adiponectin 系統卻會產生負面影響。而atorvastatin的抗發炎，抗動脈粥狀硬化的作用不會被其降低血漿中adiponectin 濃度的作用所影響。而另一研究結果顯示，在高葡萄糖情況下，會明顯促進血管平滑肌細胞的增生(proliferation)與位移(migration)。低劑量simvastatin在正常葡萄糖情況下對於VSMC生長沒有顯著抑制效果。然而，在高葡萄糖情況下，不管低劑量或高劑量simvastatin 皆可顯著抑制VSMC 生長，且抑制效果隨劑量增加而增加。作者亦發現simvastatin 可抑制Rb磷酸化，促使p53, p16, p21, p27表現，且降低 CDK2/4活性。另外，我們也發現，加入simvastatin後，會抑制MMP-2與NF-κB的活性，Rho A、cdc42、 Rac 1不受影響，Ras、c-Raf、Akt、PI3-K的活性降低，Rho B的活性增加。 總而言之， simvastatin 在模擬糖尿病之高葡萄糖狀態下會抑制VSMC增生，藉由作用於多重pRb上游步驟，包括抑制CDK2/4表現並上調p53、p21、p16、及p27而誘導G0/G1 細胞週期生長停滯。另外，我們也發現，在高葡萄糖情況下，simvastatin會透過Akt/RhoB此路徑來抑制血管平滑肌細胞的位移。
並列摘要
Diabetic patients have a two- to four-fold higher risk of developing cardiovascular diseases as compared to normal subjects. It is known that vascular smooth muscle cell (VSMC) function is highly sensitive to glucose concentration and that dysfunction of VSMCs may play a role in diabetic macrovasculopathy, including atherosclerosis. Recently, adiponectin was found to have anti-inflammation, anti-diabetic, and anti-atherosclerotic effects. Beyond lipid-lowering effects, statins have favorable effects on endothelial function. Statins stimulate nitric oxide (NO) synthase activity and mediate antioxidative effect that result in enhanced NO bioactivity, platelet adhesion, thrombosis, plaque stability, and inflammation, which may improve outcomes after PCI. It has been reported that statins can reduce intimal hyperplasia by inhibiting VSMC proliferation and migration. There is controversy about the effects of statins on plasma adiponectin, and the impact of percutaneous coronary intervention (PCI) on plasma adiponectin level is still unknown. We investigated the impact of Atorvastatin on plasma adiponectin levels in coronary artery disease (CAD) patients with stable angina and normal lipid profiles after PCI. In addition, We investigate the effect and mechanisms by which simvastatin inhibits VSMC proliferation in high glucose conditions mimicking diabetes. Our study confirmed the benefits of Atorvastatin on anti-inflammation and anti-atherosclerosis, but we also found that atorvastatin had a negative effect on the adiponectin system. The anti-inflammatory, anti-atherogenic effects of atorvastatin are not affected by decreased adiponectin levels. In another study, we found that high glucose will induce prominent proliferation and migration of vascular smooth muscle cells. Low dose of simvastatin had no significant inhibitory effect on VSMC growth in normal glucose condition. However, both low and high doses of simvastatin inhibited VSMC growth significantly in a dose-dependent manner in high glucose status. We also found that simvastatin inhibited phosphorylation of Rb, promoted expression of p53, p16, p21, p27 and decreased CDK2/4 activity. The expression of small GTPases was not affected by simvastatin; the expression of Ras, c-Raf, Akt, PI3-K, MMP-2 and NF-ΚB reduced; but the expression of Rho B increased. In conclusion, simvastatin inhibits VSMC proliferation in high glucose status, mimicking diabetes, inducing a G0/G1 phase cell cycle growth arrest by acting on multiple steps upstream of pRb, including inhibition of CDK2/4 expression and up-regulation of p53, p21, p16, and p27. Simvastatin will inhibit high glucose-medicated vascular smooth muscle cell migration via Akt/Rho B signaling pathway.
參考文獻
延伸閱讀
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