Polytarchou Christos, Papadimitriou Evangelia
Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, GR 26504, Greece.
Eur J Pharmacol. 2005 Mar 7;510(1-2):31-8. doi: 10.1016/j.ejphar.2005.01.004.
We have recently shown that superoxide and hydrogen peroxide are putative inducers of angiogenesis in vivo, possibly through up regulation of inducible nitric oxide synthase (NOS) and increased production of endogenous nitric oxide (NO). The aim of the present work was to elucidate the implication of reactive oxygen species in endothelial cell functions, using cultures of human umbilical vein endothelial cells (HUVEC). Superoxide dismutase (SOD), tempol (membrane permeable SOD mimetic) and the NADPH oxidase inhibitors, 4-(2-aminoethyl)-benzenesulfonyl fluoride and apocynin, but not allopurinol, inhibited HUVEC proliferation and migration, as well as activity of endothelial NOS (eNOS). Catalase and the intracellular hydrogen peroxide scavenger sodium pyruvate decreased, while hydrogen peroxide increased HUVEC proliferation, migration and activity of eNOS. Dexamethasone induced the proliferation and migration of HUVEC and activated eNOS. Nomega-nitro-L-arginine methyl ester (L-NAME), but not Nomega-nitro-D-arginine methyl ester, decreased endothelial cell functions and reversed the effects of dexamethasone and hydrogen peroxide. N5-(1-iminoethyl)-L-ornithine dihydrochloride, but not the inducible NOS specific inhibitor N-[[3-(aminomethyl)phenyl]methyl]-ethanimidamide dihydrochloride also decreased endothelial cell functions, similarly to L-NAME. The guanylate cyclase inhibitor 1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one inhibited HUVEC proliferation in a concentration-dependent manner and completely reversed hydrogen peroxide-induced proliferation, migration and cGMP accumulation. In conclusion, superoxide and hydrogen peroxide seem to play a significant role in promoting endothelial cell proliferation and migration, possibly through regulation of eNOS activity.
我们最近发现，超氧化物和过氧化氢可能是体内血管生成的诱导剂，可能是通过上调诱导型一氧化氮合酶（NOS）和增加内源性一氧化氮（NO）的生成来实现的。本研究的目的是利用人脐静脉内皮细胞（HUVEC）培养物来阐明活性氧在内皮细胞功能中的作用。超氧化物歧化酶（SOD）、tempol（膜通透性SOD模拟物）以及NADPH氧化酶抑制剂4-(2-氨基乙基)-苯磺酰氟和夹竹桃麻素，但不是别嘌呤醇，可抑制HUVEC的增殖、迁移以及内皮型NOS（eNOS）的活性。过氧化氢酶和细胞内过氧化氢清除剂丙酮酸钠可降低HUVEC的增殖、迁移和eNOS的活性，而过氧化氢则可增加这些指标。地塞米松可诱导HUVEC的增殖和迁移并激活eNOS。Nω-硝基-L-精氨酸甲酯（L-NAME），而非Nω-硝基-D-精氨酸甲酯，可降低内皮细胞功能并逆转地塞米松和过氧化氢的作用。N5-(1-亚氨乙基)-L-鸟氨酸二盐酸盐，而非诱导型NOS特异性抑制剂N-[[3-(氨基甲基)苯基]甲基]-乙亚胺酰胺二盐酸盐也可降低内皮细胞功能，与L-NAME类似。鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑[4,3-a]喹喔啉-1-酮以浓度依赖的方式抑制HUVEC增殖，并完全逆转过氧化氢诱导的增殖、迁移和cGMP积累。总之，超氧化物和过氧化氢似乎在促进内皮细胞增殖和迁移中发挥重要作用，可能是通过调节eNOS活性来实现的。
