Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis
Downregulation of IRS-1 expression causes inhibition of corneal angiogenesis
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DOI：
10.1167/iovs.05-0105
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发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
Behar-Cohen, F
中科院分区：
文献类型：
--
作者：
Berdugo, M;Andrieu-Soler, C;Behar-Cohen, F
目的.评价靶向胰岛素受体底物（IRS）-1的反义寡脱氧核苷酸（ODN）对大鼠角膜新生血管的抗血管生成作用。方法。用结膜下注射IRS-1反义寡核苷酸（ASODN）、IRS-1正义ODN（SODN）或PBS治疗具有新生血管的眼睛。在第一次结膜下注射后8和24小时，评价IRS-1、VEGF和IL-1 β mRNA的表达。IRS-1蛋白水平也通过蛋白质印迹分析在8小时测量（n = 4/组）。在第10天，在第4天至第9天每天处理的大鼠的平贴角膜中定量角膜新生血管。在第10天，PBS治疗的眼睛中新血管覆盖95.5% +/- 4%的角膜面积，SODN治疗的眼睛中为92% +/- 7%，ASODN治疗的眼睛中为59% +/- 20%（P < 0.001）。与对照组相比，ASODN处理组IRS-1的表达和合成显著下调。ASODN对VEGF的表达无明显影响，但在24 h显著降低IL-1 β的表达（P = 0.04）。结膜下注射IRS-1反义ODN可明显抑制大鼠角膜新生血管的形成。这种作用可能是通过下调IL-1 β介导的。IRS-1蛋白可能是胰岛素、缺氧或炎症介导的血管生成调节的有趣靶点。
PURPOSE. The antiangiogenic effect of an antisense oligodeoxynucleotide (ODN) targeting insulin receptor substrate (IRS)-1 was evaluated on rat corneal neovascularization.METHODS. Eyes with neovessels were treated with subconjunctival injections of IRS-1 antisense oligonucleotide (ASODN), IRS-1 sense ODN (SODN), or PBS. At 8 and 24 hours after the first subconjunctival injection, the expression of IRS-1, VEGF, and IL-1 beta mRNA was evaluated. IRS-1 protein levels were also measured at 8 hours by Western blot analysis ( n = 4/group). On day 10, corneal neovascularization was quantified in flat-mount corneas of rats treated daily from days 4 to 9.RESULTS. On day 10, new vessels covered 95.5% +/- 4% of the corneal area in PBS-treated eyes, 92% +/- 7% in SODN-treated eyes and 59% +/- 20% in ASODN-treated eyes ( P < 0.001). In the ASODN-treated group, the expression and synthesis of IRS-1 were significantly downregulated when compared with the control groups. ASODN did not significantly affect the expression of VEGF but significantly decreased the expression of IL-1 beta at 24 hours ( P = 0.04).CONCLUSIONS. Subconjunctival injections of IRS-1 antisense ODN significantly inhibit rat corneal neovascularization. This effect may be mediated by a downregulation of IL-1 beta. IRS-1 proteins may be interesting targets for the regulation of angiogenesis mediated by insulin, hypoxia, or inflammation.