Suppression of diabetic retinopathy with angiopoietin-1
Suppression of diabetic retinopathy with angiopoietin-1
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DOI：
10.1016/s0002-9440(10)61115-7
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发表时间：
2002-05-01
影响因子：
6
通讯作者：
Adamis, AP
中科院分区：
文献类型：
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作者：
Joussen, AM;Poulaki, V;Adamis, AP
糖尿病视网膜病变仍然是不可逆失明的主要原因。该疾病的关键早期病理学是白细胞粘附于视网膜血管，这是部分通过细胞间粘附分子-1发生的过程。一旦发生白细胞粘附，内皮细胞损伤加剧，血视网膜屏障破坏。在这里，我们表明，血管生成素-1可以预防和逆转这些糖尿病视网膜血管的变化，在新的和建立糖尿病。血管生成素-1，当玻璃体内给予新糖尿病大鼠，正常化视网膜血管内皮生长因子（VEGF）和细胞间粘附分子-1 mRNA和蛋白质水平，导致白细胞粘附减少，内皮细胞损伤，和血视网膜屏障破坏。当将编码血管生成素-1的腺病毒全身给予患有糖尿病的小鼠时，它同样可以抑制白细胞粘附、内皮细胞损伤和血视网膜屏障破坏。这些变化与视网膜eNOS、一氧化氮、Akt（蛋白激酶B）和MAP激酶活性（VEGF生物活性和白细胞粘附的已知介质）的降低一致。当内源性VEGF生物活性被可溶性Flt-1/Fc嵌合体抑制时，视网膜Akt激酶活性在体内显著降低。总之，这些数据记录了血管生成素-1的新血管和抗炎生物活性，并将其鉴定为第一种直接保护糖尿病视网膜血管的天然蛋白质。
Diabetic retinopathy remains a leading cause of irreversible blindness. A critical early pathology in the disease is the adhesion of leukocytes to the retinal vasculature, a process that occurs, in part, via intercellular adhesion molecule-1. Once leukocyte adhesion occurs, endothelial cell injury ensues, as does blood-retinal barrier breakdown. Here we show that angiopoietin-1 can prevent and reverse these diabetic retinal vascular changes in both new and established diabetes. Angiopoietin-1, when given intravitreally to newly diabetic rats, normalized retinal vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 mRNA and protein levels, leading to reductions in leukocyte adhesion, endothelial cell injury, and blood-retinal barrier breakdown. When an adenovirus coding for angiopoietin-1 was given systemically to mice with established diabetes, it similarly inhibited leukocyte adhesion and endothelial cell injury and blood-retinal barrier breakdown. These changes coincided with reductions in retinal eNOS, nitric oxide, Akt (protein kinase B), and MAP kinase activity, known mediators of VEGF bioactivity and leukocyte adhesion. When endogenous VEGF bioactivity was inhibited with a soluble Flt-1/Fc chimera, retinal Akt kinase activity was significantly reduced in vivo. Taken together, these data document new vascular and anti-inflammatory bioactivities for angiopoietin-1 and identify it as the first naturally occurring protein that directly protects the retinal vasculature in diabetes.