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5-Lipoxygenase, but not 12/15-Lipoxygenase, Contributes to Degeneration of Retinal Capillaries in a Mouse Model of Diabetic Retinopathy

Department of Pediatrics, Case Western Reserve University/Rainbow Babies and Children's Hospital, Cleveland, OH¹
Department of Medicine, Case Western Reserve University, Cleveland, OH²
Department of Internal Medicine, University of Virginia³; and
Veterans Administration Medical Center Research Service 151, Cleveland, OH⁴

Objective: Lipoxygenases are regulators of chronic inflammation 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 (WT) mice, 5-lipoxygenase-deficient (5-LO) mice, and 12/15-lipoxygenase-deficient (12-LO) 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 WT 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-LO-deficient mice, but not in 12-LO-deficient mice. Retinas from diabetic 5-LO deficient mice also had significantly less leukostasis, superoxide production and NF-kappaB expression (all p<0.006), whereas retinas from diabetic 12-LO-deficient mice had significantly less leukostasis (P<0.005) but not superoxide production or NF-kappaB expression. Retinas from diabetic wt mice were enriched with receptors for the 5-lo metabolite leukotriene b₄.

Conclusions: Diabetes-induced histological and biochemical alterations were significantly reduced in 5-LO-deficient mice, but not 12-LO-deficient mice. 5-LO represents a novel pathway for therapeutic intervention of diabetic retinopathy.

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