Abstract
Summary
Diabetic retinopathy (DR) is a leading cause of blindness primarily due to hyperpermeability and subsequent macular edema. Recent studies showed association between dyslipidemia and DR. Diabetic dyslipidemia is characterized by increased arachidonic acid which is converted to inflammatory bioactive lipids via lipoxygenases (LOX), cycloxygenase, and cytochrome P450 enzymatic pathways. Our studies focus on the role of 12/15‐LOX in DR. We have demonstrated upregulation of retinal 12/15‐LOX and its products, 12‐ and 15‐hydroxyeicosatetraenoic acids (HETEs), in retina of diabetic human and animals. Interestingly, 12‐ and 15‐HETEs were the main bioactive lipids generated in cultured human retinal endothelial cells (HREC) under hyperglycemia. Intravitreal injection of 12‐HETE induced DR phenotype in normal mice. Contrary, pharmacological inhibition or genetic deletion of 12/15‐LOX attenuated retinal hyperpermeability and inflammation in diabetic mice. 12‐ and 15‐ HETEs also disrupted HREC barrier function, increased leukocyte adhesion, migration and tube formation. This was associated with increased oxidative stress, nitric oxide generation and inflammatory cytokines. Thus, targeting 12/15‐LOX is a novel therapeutic strategy to treat DR.