Abstract 5453: Arginase I is Involved in Diabetes-Induced Vascular Endothelial Dysfunction
Arginase (A) competes with NOS for L-arginine, reducing NO production and increasing superoxide. Enhanced arginase activity also elevates levels of polyamines and proline. We have shown that enhanced arginase expression and activity contribute to vascular endothelial cell (EC) dysfunction in diabetes. We tested the hypothesis that AI and/or AII are involved in the pathology. We examined EC-dependent vasorelaxation of preconstricted aortic rings in response to acetylcholine (10−9–10−4 M) and levels of aortic arginase activity and coronary vascular fibrosis in STZ diabetic and control mice. Subgroups were wild type (WT), and double transgenic mice lacking the AII isoform (AII −/−) that either have full AI gene expression (AI+/+ AII −/−) or are partially deficient in AI genes (AI+/− AII −/−). Control WT aorta displayed a 65 + 4 % maximum relaxation response (Emax) compared to a 23 ± 5 % in diabetic WT. Emax in control AI+/+ AII −/− aorta was 66 ± 3 % vs 37 ± 4 % for diabetics; control AI +/− AII −/−aorta had an Emax of 72 ± 3 % vs. 53 ± 5 % for diabetics; Thus, EC-dependent vasorelaxation was decreased in diabetes by 49% in WT, 44% in AI +/+AII−/−, and 26% in AI+/−AII−/− (P < 0.04). Responses to the EC-independent vasodilator Na nitroprusside were similar in all groups. Aortic arginase activity levels (nmol urea/mg protein/hr) were 369, 362 and 321 in control WT, AI+/+AII −/− and AI+/−AII −/− mice, respectively. Levels were 630, 587 and 252 in diabetic WT, AI+/+AII −/− and AI+/−AII −/− mice, respectively (P < 0.02). Coronary perivascular fibrosis, assessed by Masson’s Trichrome staining of collagen, indicated a 1.89 fold higher vascular fibrosis/lumen area ratio in diabetic vs control WT mice and 1.68 fold higher in AI+/+AII −/− mice. This ratio was increased only 1.21 fold in diabetic AI +/−AII −/− mice (P < 0.03). In summary, our data indicate that diabetic AI +/−AII −/− mice exhibit less arginase activity, less impairment of ED vasodilation and less coronary vascular fibrosis than diabetic WT and AI+/+AII −/− (AII knockout) mice. Thus, arginase I activity appears to be involved in diabetes-induced vascular dysfunction.