title: Diabetes-induced vascular dysfunction involves arginase I.
abstract: Arginase can cause vascular dysfunction by competing with nitric oxide synthase for l-arginine and by increasing cell proliferation and collagen formation, which promote vascular fibrosis/stiffening. We have shown that increased arginase expression/activity contribute to vascular endothelial cell (EC) dysfunction. Here, we examined the roles of the two arginase isoforms, arginase I and II (AI and AII, respectively), in this process. Experiments were performed using streptozotocin-induced diabetic mice: wild-type (WT) mice and knockout mice lacking the AII isoform alone (AI(+/+)AII(-/-)) or in combination with partial deletion of AI (AI(+/-)AII (-/-)). EC-dependent vasorelaxation of aortic rings and arterial fibrosis and stiffness were assessed in relation to arginase activity and expression. Diabetes reduced mean EC-dependent vasorelaxation markedly in diabetic WT and AI(+/+)AII(-/-) aortas (53% and 44% vs. controls, respectively) compared with a 27% decrease in AI(+/-)AII (-/-) vessels. Coronary fibrosis was also increased in diabetic WT and AI(+/+)AII(-/-) mice (1.9- and 1.7-fold vs. controls, respectively) but was not altered in AI(+/-)AII (-/-) diabetic mice. Carotid stiffness was increased by 142% in WT diabetic mice compared with 51% in AI(+/+)AII(-/-) mice and 19% in AI(+/-)AII (-/-) mice. In diabetic WT and AI(+/+)AII(-/-) mice, aortic arginase activity and AI expression were significantly increased compared with control mice, but neither parameter was altered in AI(+/-)AII (-/-) mice. In summary, AI(+/-)AII (-/-) mice exhibit better EC-dependent vasodilation and less vascular stiffness and coronary fibrosis compared with diabetic WT and AI(+/+)AII(-/-) mice. These data indicate a major involvement of AI in diabetes-induced vascular dysfunction.
authors: Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, 30912, USA.
authors: Maritza J
authors: MJ
authors: Romero
authors: Jennifer A
authors: JA
authors: Iddings
authors: Daniel H
authors: DH
authors: Platt
authors: M Irfan
authors: MI
authors: Ali
authors: Stephen D
authors: SD
authors: Cederbaum
authors: David W
authors: DW
authors: Stepp
authors: Ruth B
authors: RB
authors: Caldwell
authors: Robert W
authors: RW
authors: Caldwell
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000503:physiopathology; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D001158:Arteries / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D002339:Carotid Arteries / Q000201:enzymology / Q000503:physiopathology; D003187:Compliance; D003331:Coronary Vessels / Q000201:enzymology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D006861:Hydrogen Peroxide / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; D006861:Hydrogen Peroxide; C544448:Arg1 protein, mouse; C481673:Arg2 protein, mouse; D001119:Arginase; D006909:Hydroxyproline