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Shawn C. Elms, William Caldwell, Haroldo A. Toque, Ruth Caldwell; Arginase Inhibitors As Potential Therapy For Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3286.
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Ischemic injury and endothelial dysfunction are prominent features of diabetic retinopathy (DR), but the molecular mechanisms of the damage are not understood. In healthy individuals, nitric oxide (NO) produced by NO synthase (NOS) maintains normal blood flow and endothelial function. The urea cycle enzyme arginase (Arg) can limit NO formation by competing for L-arginine, a co-substrate for both enzymes. Our objective is to investigate the role of Arg in the diabetes-induced retinal vascular dysfunction of DR.
Using a novel mouse funduscope capable of imaging the retinal microcirculation down to 2.25 microns, we measured retinal vessel diameter change to endothelial dependent and independent vasodilators in streptozotocin (STZ)-induced diabetic and normoglycemic control mice treated with an arginase inhibitor or lacking one copy of the Arg 1 gene (Arg1+/-). We also examined Arg protein expression/activity in diabetic and control retinas.
Our studies showed that endothelial dependent retinal artery relaxation is markedly impaired in diabetic mice (60% of normoglycemic control), while Arg activity and expression are increased. The diabetes-induced vascular dysfunction was largely prevented in mice treated with specific Arg inhibitors (BEC and ABH) or in Arg1+/- mice (85% of control), thus indicating Arg as a mediator of diabetes-induced retinal endothelial dependent vascular dysfunction.
Our data indicate that increases in Arg protein/activity are involved in diabetic retinal vascular dysfunction. The specific Arg inhibitors BEC and ABH cause an improvement in vascular function in response to diabetic insult. Using this novel imaging technology to measure vascular function in vivo in conjunction with Arg inhibitors offers a novel methodology for pharmacological research on retinal microvascular disease.
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