Genistein及Magnolol抑制血管平滑肌細胞增生之研究—與Heme oxygenase-1之相關性

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Title:	Genistein及Magnolol抑制血管平滑肌細胞增生之研究—與Heme oxygenase-1之相關性 Genistein and Magnolol protect against smooth muscle cell proliferation by upregulating heme oxygenase-1
Authors:	陳紀方;Ji-Fang Chen
Contributors:	藥學院中國藥學研究所碩士班
Keywords:	第一型血基質氧化酶異黃酮;厚朴酚;HO-1;genistein;magnolol
Date:	2010
Issue Date:	2010-09-29 14:09:40 (UTC+8)
Abstract:	摘要 Genistein是一種常見的異黃酮（Isoflavone），它可以藉由攝食多種植物來取得，尤其是豆科植物。根據過去的研究，genistein會藉由生長因子的調控而影響致癌基因抑制腫瘤發生，以及細胞的增生、血管新生和訊息傳遞的發生。Genistein在胞內系統多種反應被認為可以抑制酪胺酸蛋白激酶（protein-tyrosine kinases, PTKs）的活化。厚朴酚（Magnolol）是厚朴的主要成份，它具有抗癌、抗氧化、抗發炎、止痛、舒張血管平滑肌及抗血小板凝集的作用。第一型血基質氧化酶（Heme oxygenase-1, HO-1），具有抗氧化以及組織保護的功用。增加HO-1蛋白質的表現，伴隨著血基質（heme）的降解，會產生一氧化碳（carbon monoxide, CO）、膽黃素（bilirubin）和鐵離子（Fe2+）。這些產物中，膽黃素（bilirubin）具有抗氧化劑功能，一氧化碳（CO）則透過血管擴張及抗血小板凝集作用來達到保護組織的作用。根據過去的研究顯示：誘發血管平滑肌細胞和內皮細胞中，被誘導出來的HO-1可用來抑制內皮細胞的增生。因此，本研究目的為探討genistein以及magnolol是否可藉由調控HO-1蛋白質表現進而抑制血管平滑肌細胞增生的作用。研究結果發現，genistein (5,10, 20 uM)和magnolol（5, 10, 20 uM）可明顯抑制FBS 誘發血管平滑肌細胞的增生現象，且具有劑量依存性。除此之外，genistein 具有調控HO-1蛋白質作用，隨著genistein濃度的增加（5, 10, 20 M），HO-1蛋白質的表現也明顯增加，且在genistein濃度20 M時，HO-1蛋白質表現達到最大；另外，genistein對p44/42 MAPK蛋白質調控研究也發現，genistein (5, 10, 20 uM)可明顯增加p44/42 MAPK磷酸化作用，且在genistein (10 M) 時其磷酸化達最大，但對p38 MAPK及JNK MAPK並無影響。此外以magnolol（5, 10, 20 uM）實驗發現，magnolol亦可增加HO-1蛋白質的表現以及p44/42 MAPK磷酸化的作用，且此作用也呈現劑量依存性的現象。由以上初步結果顯示，genistein與magnolol均可呈劑量依存性抑制FBS誘發血管平滑肌細胞增生，然此抑制作用可能與活化p44/42 MAPK pathway，及增加HO-1蛋白質表現有關，至於此二藥物如何調控HO-1的訊息傳遞路徑則有待進一步研究分析。 Abstract The isoflavone genistein (4’,5,7-trihydroxyisoflavone) is a dietary-derived natural product present in a variety of plant foods that selectively inhibit the activity of protein-tyrosine kinases. Genistein affects oncogene-induced tumorigenesis, cell proliferation, cell differentiation, angiogenesis, and signal transduction mechanisms activated by growth factors. The multiple effects of genistein in cellular systems are presumed to reflect its ability to inhibit the activity of protein-tyrosine kinase. Magnolol is a major component of Magnolia officinalis, and has been reported to have various biological effects, including anti-carcinogenicity, antioxidant activity, anti-inflammatory and analgesic effects, smooth muscle relaxant activity, and antithrombotic effect. Heme oxygenase-1(HO-1) has emerged recently as a crucial mediator of antioxidant and tissue protective action. Increased HO-1 expression leads to degradation of heme and accumulation of iron, bilirubin, and carbon monoxide (CO). Of these metabolites, bilirubin acts as a direct antioxidant, whereas CO may exert tissue-protective actions primarily through its vasodilator and antiplatelet effects. HO-1 can be induced in vascular smooth muscle cells and endothelial cells and functions as an endogenous inhibitor of vascular smooth muscle cells proliferation. To address the role of HO-1 in the anti-proliferation of genistein, we evaluate the effect of genistein in the expression of HO-1 protein in vascular smooth muscle cells. The results had shown that genistein significantly inhibit the proliferation of vascular smooth muscle cells induced by FBS. Meanwhile, genistein (5, 10, 20 uM) significantly increased the expression of HO-1 protein and the phosphorylation of p44/42 MAPK in vascular smooth muscle cells. Furthermore, it had shown that magnolol (5, 10, 20 uM) had similar effect on the anti-proliferation, the expression of HO-1 protein as well as the activation of p44/42 MAPK in vascular smooth muscle cells. In conclusion, both of genistein and magnolol exert the anti-proliferation effect may associated with the expression of HO-1 and the activation of p44/42 MAPK in vascular smooth muscle cells. Further studies are needed to clarify how genistein and magnolol induced the expression of HO-1 in vascular smooth muscle cells.
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