5-lipoxygenase, but not 12/15-lipoxygenase, contributes to degeneration of retinal capillaries in a mouse model of diabetic retinopathy
5-lipoxygenase, but not 12/15-lipoxygenase, contributes to degeneration of retinal capillaries in a mouse model of diabetic retinopathy
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DOI：
10.2337/db07-1217
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发表时间：
2008-05-01
期刊：
影响因子：
7.7
通讯作者：
Kern, Timothy S.
中科院分区：
文献类型：
--
作者：
Gubitosi-Klug, Rose A.;Talahalli, Ramaprasad;Kern, Timothy S.
抗氧化脂氧合酶是慢性炎症和氧化应激产生的调节剂。我们评估了5-和12-脂氧合酶在糖尿病视网膜病变发展中的作用。研究设计和方法-野生型小鼠，5-脂氧合酶缺陷小鼠，和12/15-脂氧合酶缺陷小鼠进行评估，1）糖尿病9个月后视网膜组织病理学和白三烯受体表达，2）糖尿病3个月后白细胞停滞和视网膜超氧化物生成。型小鼠出现了预期的视网膜毛细血管和周细胞变性，白细胞停滞和超氧化物产生增加（P <0.006）。我们在这些动物中没有发现糖尿病诱导的视网膜神经节细胞变性的证据。在5-脂氧合酶缺陷小鼠中，血管组织病理学显著抑制，但在12/15-脂氧合酶缺陷小鼠中没有。糖尿病5-脂氧合酶缺陷小鼠的视网膜也具有显著更少的白细胞停滞、超氧化物产生和核因子-κ B（NF-κ B）表达（均P <0.006），而糖尿病12/15-脂氧合酶缺陷小鼠的视网膜具有显著更少的白细胞停滞（P <0.005），但不具有超氧化物产生或NF-κ B表达。糖尿病野生型小鼠的视网膜富含5-脂氧合酶代谢产物白三烯B-4的受体。糖尿病诱导的组织学和生化变化显着减少5-脂氧合酶缺陷的小鼠，但不是12/15-脂氧合酶缺陷mice. CONCLUSIONS-5-脂氧合酶是一种新的途径，用于治疗干预糖尿病视网膜病变。
OBJECTIVE-Lipoxygenases are regulators of chronic inflamation and oxidative stress generation. We evaluated the role of 5-and 12-lipoxygenases in the development of diabetic retinopathy.RESEARCH DESIGN AND METHODS-Wild-type mice, 5-li-poxygenase- deficient mice, and 12/15-lipoxygenase- deficient mice were assessed 1) after 9 months of diabetes for retinal histopathology and leukotriene receptor expression and 2) after 3 months of diabetes for leukostasis and retinal superoxide generation.RESULTS-Diabetic wild-type mice developed the expected degeneration of retinal capillaries and pericytes and increases in both leukostasis and superoxide production (P < 0.006). We found no evidence of diabetes-induced degeneration of retinal ganglion cells in these animals. The vascular histopathology was significantly inhibited in 5-li-poxygenase- deficient mice, but not in 12/15-lipoxygenase- deficient mice. Retinas from diabetic 5-li-poxygenase- deficient mice also had significantly less leukostasis, superoxide production, and nuclear factor-kappa B (NF-kappa B) expression (all P < 0.006), whereas retinas from diabetic 12/15-lipoxygenase- deficient mice had significantly less leukostasis (P < 0.005) but not superoxide production or NF-kappa B expression. Retinas from diabetic wild-type mice were enriched with receptors for the 5-lipoxygenase metabolite leukotriene B-4. Diabetes-induced histological and biochemical alterations were significantly reduced in 5-li-poxygenase- deficient mice, but not 12/15-lipoxygenase- deficient mice.CONCLUSIONS-5-Lipoxygenase represents a novel pathway for therapeutic intervention of diabetic retinopathy.