一种新黄酮类化合物（(2S)-8-异戊烯基-7，2',4'-三羟基5-甲氧基二氢黄酮）的抗血管生成作用及其机制研究
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摘要
血管生成以内皮细胞活化、细胞外基质降解、内皮细胞迁移、增殖、最终形成血管样结构为主要特征,是受多种因素调节的复杂的生理和病理过程。天然黄酮类化合物是植物体多酚类的内信号分子及中间体或代谢物,种类繁多,结构复杂,具有广谱的药理活性和较低毒性,对于人类肿瘤,心血管疾病等病的治疗和预防有重要意义。本文探讨从苦参中提取的黄酮类化合物(2S)-8-异戊烯基-7,2′,4′-三羟基5-甲氧基二氢黄酮(SF-45)对血管生成的影响及作用机理。
结果表明：(1)10μg/ml的SF-45不影响ECV304细胞的增殖,但是当其浓度达到20μg/ml时对ECV304细胞的增殖表出现为促进作用,当浓度达到30,40,50μg/ml时有明显的抑制作用；(2)同样低浓度的SF-45(10、20、30μg/ml)对ECV304细胞的迁移没有明显的作用,当浓度达到40,50μg/ml时,出现明显的抑制作用；(3)SF-45对于ECV304细胞粘附抑制作用较为明显,呈现浓度依赖性,在10μg/ml时就有明显的抑制作用,浓度升高,抑制作用加强,到50gg/ml时抑制作用最强；(4)SF-45对于ECV304细胞的管样结构的形成同样有明显的抑制作用,在10,20μg/ml时,抑制作用较为明显,当浓度达到30、40、50μg/ml时,抑制作用最强；(5)SF-45抑制鸡胚尿囊膜(chicken chorillantoic membrances,CAM)在体实验模型的血管生成,同对照组比较,加药组的血管粗细和密度都呈现抑制作用；(6)SF-45对ECV304细胞内的活性氧(reactive oxygen species,ROS)的影响同样是低浓度10μg/ml时没有明显的作用,随着浓度的增高,在20、30、40、50μg/ml各个浓度都出现了明显的抑制作用；(7)SF-45对于细胞内血管内皮生长因子(vascular endothelial growth factor, VEGF)表达的影响无浓度依赖性,在10gg/ml时就已经出现明显的抑制作用,到20μg/ml时,抑制作用达到最强,30、40、50μg/ml时的抑制作用与20μg/ml时的作用无明显差异；(8)流式细胞术分析表明,SF-45可以引起ECV304细胞周期阻滞在G1期。
结论：(1)SF-45可以在体外抑制ECV304细胞增殖、迁移、粘附以及管样结构形成,并在体内试验模型鸡胚尿囊膜中,具有抗血管生成作用；(2)SF-45可能通过抑制细胞内ROS生成和VEGF表达,发挥抗血管生成作用。总之,许多疾病如肿瘤、慢性炎症、糖尿病等的发生发展都依赖于血管生成,因此抑制血管生成有助于这些疾病的治疗；而对于许多缺血性疾病如冠状动脉缺血、急性下肢缺血和脑梗塞等来说,通过促进血管生成可使症状改善。本研究结果表明SF45值得作为一种潜在的抗血管生成药物进行进一步深入研究。
Angiogenesis is a complex physiological and pathological process that includes activation of endothelial cells by growth factors, followed by enzymatic degradation of basement membrane, detachment of endothelial cells from adhesion proteins, endothelial cells migration into the perivascular spaces and proliferation, and finally new vessels formation. Flavonoids are signaling molecules, intermediates and metabolites of plant polyphenolic compounds with a wide range of complex structure. They have important significance on treatment of human tumor and cardiovascular diseases, as wide pharmacological activity and low toxicity. In this study, we conducted detailed studies to explore the effect of a new flavoiioid(2S)-8-isopentenyl-7,2',4'-trihydroxy-5-methoxyflavonone(SF-45) on angiogenesis and its mechanism.
Results:(1) SF-45 exhibited no inhibitory effect on endothelial cells (EcV304) proliferation under 10μg/ml treatment, whereas promoted cell proliferation slightly (p<0.05) under 20μg/ml,.However SF-45 exhibited the inhibition effect under 30,40 and 50μg/ml. (2) Low concentrations (10,20,30μg/ml) of SF-45 had no effect on migration of EcV304 cells, while higher concentrations (40 and 50μg/ml) of SF-45 remarkably inhibited cell migration. (3) SF-45 significantly inhibited ECV304 cell adhesion in a concentration-dependent manner.10μg/ml of SF-45 had obviously induced cell adhesion, and the maximal effect achieved at 50μg/ml. (4) SF-45 significantly inhibited the tube formation in a concentration-dependent manner.10 and 20μg/ml of SF-45 obviously inhibited tube formation, and the maximal effect achieved at 30、40 and 50μg/ml. (5) SF-45 also exhibited antiangiogenesis effect in vivo, gave a less degree of thickness and density of blood vessels compared to control in chicken chorillantoic membrances experiment. (6) 10μg/ml of SF-45 had no effect on the intracellular ROS level. However, high concentration of SF-45 (20、30、40 and 50μg/ml) could obviously reduce ROS generation in ECV304 cells. (7) SF-45 down-regulated VEGF expression without concentration-dependent manner.10μg/ml of SF-45 obviously inhibited the expression of VEGF, and it reached inhibitory the maximal effect at 20μg/ml. However, the inhibition effect under 30,40,50μg/ml treatment had no remarkably difference with 20μg/ml. (8) SF-45 arrested ECV304 cell cycle in G1 phase.
Conclusions:(1) According to the inhibitory effect on endothelial cell proliferation, migration, adhesion and tube formation in vitro, and the antiangiogenesis effect in CAM test, we concluded that SF-45 exhibited antiangiogenesis effect both in vitro and in vivo. (2) The mechanism might relate to its antioxidative activity, which further resulted in the inhibition of ROS-associated VEGF expression. On the whole, many diseases, such as cancer, chronic inflammation and diabetes, are dependent on angiogensis, so these diseases may benefit from therapeutic inhibiton of angiogensis. While in many ischemic diseases, such as ischemic coronary artery diseases, critical limb ischemia and brain infarction, angiogensis may be favorable to improve these diseases. The results of the present study suggested that SF-45 is worth to undergo the further study as a potential new drug candidate of anti-angiogenesis.
结果表明：(1)10μg/ml的SF-45不影响ECV304细胞的增殖,但是当其浓度达到20μg/ml时对ECV304细胞的增殖表出现为促进作用,当浓度达到30,40,50μg/ml时有明显的抑制作用；(2)同样低浓度的SF-45(10、20、30μg/ml)对ECV304细胞的迁移没有明显的作用,当浓度达到40,50μg/ml时,出现明显的抑制作用；(3)SF-45对于ECV304细胞粘附抑制作用较为明显,呈现浓度依赖性,在10μg/ml时就有明显的抑制作用,浓度升高,抑制作用加强,到50gg/ml时抑制作用最强；(4)SF-45对于ECV304细胞的管样结构的形成同样有明显的抑制作用,在10,20μg/ml时,抑制作用较为明显,当浓度达到30、40、50μg/ml时,抑制作用最强；(5)SF-45抑制鸡胚尿囊膜(chicken chorillantoic membrances,CAM)在体实验模型的血管生成,同对照组比较,加药组的血管粗细和密度都呈现抑制作用；(6)SF-45对ECV304细胞内的活性氧(reactive oxygen species,ROS)的影响同样是低浓度10μg/ml时没有明显的作用,随着浓度的增高,在20、30、40、50μg/ml各个浓度都出现了明显的抑制作用；(7)SF-45对于细胞内血管内皮生长因子(vascular endothelial growth factor, VEGF)表达的影响无浓度依赖性,在10gg/ml时就已经出现明显的抑制作用,到20μg/ml时,抑制作用达到最强,30、40、50μg/ml时的抑制作用与20μg/ml时的作用无明显差异；(8)流式细胞术分析表明,SF-45可以引起ECV304细胞周期阻滞在G1期。
结论：(1)SF-45可以在体外抑制ECV304细胞增殖、迁移、粘附以及管样结构形成,并在体内试验模型鸡胚尿囊膜中,具有抗血管生成作用；(2)SF-45可能通过抑制细胞内ROS生成和VEGF表达,发挥抗血管生成作用。总之,许多疾病如肿瘤、慢性炎症、糖尿病等的发生发展都依赖于血管生成,因此抑制血管生成有助于这些疾病的治疗；而对于许多缺血性疾病如冠状动脉缺血、急性下肢缺血和脑梗塞等来说,通过促进血管生成可使症状改善。本研究结果表明SF45值得作为一种潜在的抗血管生成药物进行进一步深入研究。
Angiogenesis is a complex physiological and pathological process that includes activation of endothelial cells by growth factors, followed by enzymatic degradation of basement membrane, detachment of endothelial cells from adhesion proteins, endothelial cells migration into the perivascular spaces and proliferation, and finally new vessels formation. Flavonoids are signaling molecules, intermediates and metabolites of plant polyphenolic compounds with a wide range of complex structure. They have important significance on treatment of human tumor and cardiovascular diseases, as wide pharmacological activity and low toxicity. In this study, we conducted detailed studies to explore the effect of a new flavoiioid(2S)-8-isopentenyl-7,2',4'-trihydroxy-5-methoxyflavonone(SF-45) on angiogenesis and its mechanism.
Results:(1) SF-45 exhibited no inhibitory effect on endothelial cells (EcV304) proliferation under 10μg/ml treatment, whereas promoted cell proliferation slightly (p<0.05) under 20μg/ml,.However SF-45 exhibited the inhibition effect under 30,40 and 50μg/ml. (2) Low concentrations (10,20,30μg/ml) of SF-45 had no effect on migration of EcV304 cells, while higher concentrations (40 and 50μg/ml) of SF-45 remarkably inhibited cell migration. (3) SF-45 significantly inhibited ECV304 cell adhesion in a concentration-dependent manner.10μg/ml of SF-45 had obviously induced cell adhesion, and the maximal effect achieved at 50μg/ml. (4) SF-45 significantly inhibited the tube formation in a concentration-dependent manner.10 and 20μg/ml of SF-45 obviously inhibited tube formation, and the maximal effect achieved at 30、40 and 50μg/ml. (5) SF-45 also exhibited antiangiogenesis effect in vivo, gave a less degree of thickness and density of blood vessels compared to control in chicken chorillantoic membrances experiment. (6) 10μg/ml of SF-45 had no effect on the intracellular ROS level. However, high concentration of SF-45 (20、30、40 and 50μg/ml) could obviously reduce ROS generation in ECV304 cells. (7) SF-45 down-regulated VEGF expression without concentration-dependent manner.10μg/ml of SF-45 obviously inhibited the expression of VEGF, and it reached inhibitory the maximal effect at 20μg/ml. However, the inhibition effect under 30,40,50μg/ml treatment had no remarkably difference with 20μg/ml. (8) SF-45 arrested ECV304 cell cycle in G1 phase.
Conclusions:(1) According to the inhibitory effect on endothelial cell proliferation, migration, adhesion and tube formation in vitro, and the antiangiogenesis effect in CAM test, we concluded that SF-45 exhibited antiangiogenesis effect both in vitro and in vivo. (2) The mechanism might relate to its antioxidative activity, which further resulted in the inhibition of ROS-associated VEGF expression. On the whole, many diseases, such as cancer, chronic inflammation and diabetes, are dependent on angiogensis, so these diseases may benefit from therapeutic inhibiton of angiogensis. While in many ischemic diseases, such as ischemic coronary artery diseases, critical limb ischemia and brain infarction, angiogensis may be favorable to improve these diseases. The results of the present study suggested that SF-45 is worth to undergo the further study as a potential new drug candidate of anti-angiogenesis.
引文
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