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

¹ Department of Pediatrics, Case Western Reserve University/Rainbow Babies and Children's Hospital, Cleveland, Ohio
² Department of Medicine, Case Western Reserve University, Cleveland, Ohio
³ Department of Internal Medicine, University of Virginia, Charlottesville, Virginia
⁴ Veterans Administration Medical Center Research Service 151, Cleveland, Ohio

Corresponding author: Rose Gubitosi-Klug, MD, PhD, Division of Pediatric Endocrinology and Metabolism, Case Medical Center, 11100 Euclid Ave., Rainbow Babies and Children's Hospital, Room 737, Cleveland, OH 44106. E-mail: rose.gubitosi-klug{at}case.edu

Abbreviations: ICAM, intracellular adhesion molecule; LT, leukotriene; NF-B, nuclear factor-B; 12S-HETE, 12S-hydroxy-5,8,10,14-eicosatetraenoic acid

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-lipoxygenase–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-lipoxygenase–deficient mice, but not in 12/15-lipoxygenase–deficient mice. Retinas from diabetic 5-lipoxygenase–deficient mice also had significantly less leukostasis, superoxide production, and nuclear factor-B (NF-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- B expression. Retinas from diabetic wild-type mice were enriched with receptors for the 5-lipoxygenase metabolite leukotriene B₄. Diabetes-induced histological and biochemical alterations were significantly reduced in 5-lipoxygenase–deficient mice, but not 12/15-lipoxygenase–deficient mice.

CONCLUSIONS—5-Lipoxygenase represents a novel pathway for therapeutic intervention of diabetic retinopathy.

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