Viita Helena, Markkanen Johanna, Eriksson Emmi, Nurminen Markku, Kinnunen Kati, Babu Mohan, Heikura Tommi, Turpeinen Sanna, Laidinen Svetlana, Takalo Teemu, Ylä-Herttuala Seppo
Department of Biotechnology and Molecular Medicine, University of Kuopio, Finland.
Circ Res. 2008 Feb 1;102(2):177-84. doi: 10.1161/CIRCRESAHA.107.155556. Epub 2007 Nov 8.
Human 15-lipoxygenase-1 (15-LO-1) is an oxidizing enzyme capable of producing reactive lipid hydroperoxides. 15-LO-1 and its products have been suggested to be involved in many pathological conditions, such as inflammation, atherogenesis, and carcinogenesis. We used adenovirus-mediated gene transfers to study the effects of 15-LO-1 on vascular endothelial growth factor (VEGF)-A165- and placental growth factor (PlGF)-induced angiogenesis in rabbit skeletal muscles. 15-LO-1 significantly decreased all angiogenic effects induced by these growth factors, including capillary perfusion, vascular permeability, vasodilatation, and an increase in capillary number. The effects are attributable to the reduction in the amount of VEGF-A165 and PlGF transcripts by 15-LO-1, resulting in reduced protein expression. The most likely mediator of the VEGF family-induced capillary vasodilatation is nitric oxide (NO), which is produced by NO synthases. Endothelial NO synthase protein expression and NO synthase activity were significantly induced by VEGF-A165, and these inductions were reduced by 15-LO-1. VEGF-A165 induces its angiogenic effects primarily via vascular endothelial growth factor receptor (VEGFR)2, and also PlGF mediates angiogenic signaling via VEGFR2, even though it binds to VEGFR1. VEGFR2 expression is induced by peroxisome proliferator-activating receptor . We showed by quantitative RT-PCR and immunohistochemistry that expression of endogenous rabbit peroxisome proliferator-activating receptor and VEGFR2 were significantly increased in the growth factor-transduced muscles, but these inductions were efficiently prevented by 15-LO-1. In conclusion, the results suggest that expression of 15-LO-1 has an efficient antiangiogenic effect in vivo via reduction in growth factor mRNA levels, NO bioactivity, and VEGFR2 expression.
人15-脂氧合酶-1（15-LO-1）是一种能够产生反应性脂质氢过氧化物的氧化酶。15-LO-1及其产物被认为与许多病理状况有关，如炎症、动脉粥样硬化和癌症发生。我们利用腺病毒介导的基因转移来研究15-LO-1对兔骨骼肌中血管内皮生长因子（VEGF）-A165和胎盘生长因子（PlGF）诱导的血管生成的影响。15-LO-1显著降低了这些生长因子诱导的所有血管生成效应，包括毛细血管灌注、血管通透性、血管舒张以及毛细血管数量的增加。这些效应归因于15-LO-1使VEGF-A165和PlGF转录本数量减少，从而导致蛋白表达降低。VEGF家族诱导的毛细血管舒张最可能的介质是一氧化氮（NO），它由一氧化氮合酶产生。VEGF-A165显著诱导内皮型一氧化氮合酶蛋白表达和一氧化氮合酶活性，而15-LO-1可降低这些诱导作用。VEGF-A165主要通过血管内皮生长因子受体（VEGFR）2诱导其血管生成效应，并且PlGF也通过VEGFR2介导血管生成信号，尽管它与VEGFR1结合。VEGFR2的表达由过氧化物酶体增殖物激活受体诱导。我们通过定量逆转录聚合酶链反应（RT-PCR）和免疫组织化学表明，在生长因子转导的肌肉中，内源性兔过氧化物酶体增殖物激活受体和VEGFR2的表达显著增加，但15-LO-1可有效阻止这些诱导作用。总之，结果表明15-LO-1的表达通过降低生长因子mRNA水平、NO生物活性和VEGFR2表达在体内具有有效的抗血管生成作用。
