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Arginase 1 as a Therapeutic Target in Diabetic Retinopathy
Author(s) -
Elms Shawn Christopher,
Flores-Toque Haroldo,
Caldwell R William,
Caldwell Ruth
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.840.12
Subject(s) - arginase , diabetic retinopathy , diabetes mellitus , retinal , endothelial dysfunction , medicine , nitric oxide , retinopathy , endocrinology , nitric oxide synthase , microcirculation , retina , pharmacology , arginine , chemistry , biology , biochemistry , ophthalmology , amino acid , neuroscience
Objective Ischemic injury is a prominent feature of diabetic retinopathy (DR), but the underlying molecular mechanisms are not understood. In healthy individuals, nitric oxide (NO) produced by NO synthase (NOS) maintains normal blood flow. The urea cycle enzyme arginase (Arg) can limit NO formation by competing for L‐arginine, a substrate for both enzymes. Our objective is to investigate the role of Arg in diabetes‐induced retinal vascular dysfunction. Method Using a novel mouse funduscope capable of imaging the retinal microcirculation, we examined the role of Arg expression/activity in STZ diabetes‐ induced retinal vascular dysfunction. Results Our studies showed that endothelial dependent vasorelaxation is markedly impaired in arterioles of STZ diabetic mice (60% of control) as Arg activity and expression are increased. The vascular dysfunction is largely prevented in Arg I+/− mice (85% of control) or mice treated with the specific Arg inhibitor ABH, thus indicating Arg as a mediator of diabetes‐induced decreases in endothelial dependent vasorelaxation. Conclusion Our data indicate that increases in Arg protein/activity are involved in diabetes‐induced retinal vascular dysfunction. Using this novel imaging technology to measure vascular function in vivo in conjunction with arginase inhibitors offers a novel methodology for pharmacological research on retinal microvascular disease.