D020 The polyphenol curcumin inhibits in vitro angiogenesis and cyclic nucleotide phosphodiesterases (PDEs) activities similarly to PDE inhibitors
D020 The polyphenol curcumin inhibits in vitro angiogenesis and cyclic nucleotide phosphodiesterases (PDEs) activities similarly to PDE inhibitors
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D020 多酚姜黄素可抑制体外血管生成和环核苷酸磷酸二酯酶 (PDE) 活性，与 PDE 抑制剂类似
DOI：
10.1016/s1875-2136(09)72230-2
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发表时间：
2009
影响因子：
3
通讯作者：
C. Lugnier
中科院分区：
文献类型：
--
作者：
A. Abusnina;T. Keravis;C. Lugnier
VEGF通过刺激内皮细胞迁移、增殖和分化，在血管生成中起主要作用。已知细胞内cAMP的增加抑制基础以及VEGF诱导的内皮细胞增殖。环核苷酸磷酸二酯酶（cyclicnucleotidephosphodiesterases，PDE）是一类特异性水解环核苷酸的酶，在信号转导中起着重要作用。我们的团队先前已经报道，人脐静脉内皮细胞（HUVEC）中的PDE 2和PDE 4上调（活性、蛋白质和mRNA）与VEGF诱导的血管生成有关，并且PDE 2和PDE 4同工酶活性的抑制通过增加cAMP水平、通过抑制细胞增殖、细胞迁移和细胞周期进程来防止血管生成的发展（Favot et al.，Thromb Haemost 2003，90：334和2004，92：634）。另一方面，我们已经表明多酚抑制PDE（Orallo等人，Naunyn Schmiedebergs Arch Pharmacol 2004，370：452; Planta Med 2005，71：99; Alvarez等人，Br J药效学. 2006，147：269）。从植物姜黄中分离出的多酚姜黄素存在于咖喱粉中，并且已知具有抗炎、抗氧化和抗癌特性。姜黄素的抗癌特性已在动物中通过其抑制肿瘤发生和肿瘤进展的能力得到证实。因此，本研究的目的是研究PDE参与姜黄素的抗血管生成特性。通过测定从血管组织中纯化的五种同工酶PDE 1-PDE 5的IC 50值来评估姜黄素对PDE活性的影响。姜黄素对PDE 1、PDE 2、PDE 3和PDE 4有抑制作用，IC 50值在10 ~ 20 μm之间，对PDE 5有抑制作用，IC 50值为35 μm。浓度为10μm的姜黄素抑制基础和VEGF刺激的HUVEC增殖（分别为58%和54%，P=0.003）。此外，10μm姜黄素显著抑制（52%，P=0.001）VEGF诱导的HUVEC迁移，与选择性PDE 2抑制剂（0.1μm BAY-60-7550，69%，P=0.003）和选择性PDE 4抑制剂（10μm咯利普兰，41%，P=0.006）相似。这些结果首次显示姜黄素抑制PDE活性，表明存在于食物中的姜黄素可能通过抑制PDE活性在内皮细胞水平抑制血管生成。
VEGF, by stimulating endothelial cells to migrate, proliferate and differentiate, plays a major role in angiogenesis. Increase in intracellular cAMP is known to inhibit basal as well as VEGF-induced endothelial cell proliferation. Cyclic nucleotide phosphodiesterases (PDEs) play a key role in signal transduction by hydrolyzing specifically cyclic nucleotides. Our team has previously reported that PDE2 and PDE4 up-regulations (activity, protein and mRNA) in human umbilical vein endothelial cells (HUVECs) are implicated in VEGF-induced angiogenesis and that inhibition of PDE2 and PDE4 isozyme activities prevents the development of angiogenesis by increasing cAMP level, by inhibiting cell proliferation, cell migration and cell cycle progression (Favot et al., Thromb Haemost 2003, 90: 334 and 2004, 92: 634). On another hand, we have shown that polyphenols inhibit PDEs (Orallo et al., Naunyn Schmiedebergs Arch Pharmacol 2004, 370: 452; Planta Med 2005, 71: 99; Alvarez et al., Br J Pharmacol. 2006, 147: 269). The polyphenol curcumin, isolated from the plant Curcuma longa, is present in curry powder, and is known to have anti-infl ammatory, anti-oxidant and anti-cancer properties. The anti-carcinogenic properties of curcumin have been demonstrated in animals by its ability to inhibit tumor initiation and tumor progression. Therefore, this study was aimed to investigate the participation of PDEs in anti-angiogenic properties of curcumin. The effect of curcumin on PDE activities was assessed by the determination of IC50 values on the five isozymes PDE1-PDE5 purified from vascular tissues. Curcumin was able to inhibit PDE1, PDE2, PDE3 and PDE4 with IC50 values in the range of 10 to20μm, and PDE5 with an IC50 value of35μm. Curcumin at a concentration of 10μm inhibited both basal and VEGF-stimulated HUVEC proliferation (58 %and 54 %respectively, P=0.003). Furthermore, 10μm curcumin inhibited significantly (52 %, P=0.001) VEGF-induced HUVEC migration similarly to the selective PDE2 inhibitor (0.1μm BAY-60-7550, 69 %, P=0.003) and the selective PDE4 inhibitor (10μm rolipram, 41 %, P=0.006)). These results, showing for the first time that curcumin inhibits PDE activities, suggest that curcumin present in food might inhibit angiogenesis at endothelial cell level by inhibiting PDE activities.