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 ϩ/ϩ AII Ϫ/Ϫ ) or in combination with partial deletion of AI (AI ϩ/Ϫ AII Ϫ/Ϫ ). EC-dependent vasorelaxation of aortic rings and arterial fibrosis and stiffness were assessed in relation to arginase activity and expression. Diabetes reduced mean ECdependent vasorelaxation markedly in diabetic WT and AI ϩ/ϩ AII mice. In diabetic WT and AI ϩ/ϩ AII Ϫ/Ϫ mice, aortic arginase activity and AI expression were significantly increased compared with control mice, but neither parameter was altered in AI ϩ/Ϫ AII Ϫ/Ϫ mice. In summary, AI ϩ/Ϫ AII Ϫ/Ϫ mice exhibit better EC-dependent vasodilation and less vascular stiffness and coronary fibrosis compared with diabetic WT and AI ϩ/ϩ AII Ϫ/Ϫ mice. These data indicate a major involvement of AI in diabetes-induced vascular dysfunction. fibrosis; oxidative stress; vascular stiffness IN VASCULAR ENDOTHELIAL CELLS (ECs), nitric oxide (NO) synthase (NOS) uses L-arginine to produce NO, which maintains blood flow and reduces inflammation (21,22). Reduced availability of L-arginine to NOS and the resultant reduction of NO production have been implicated in the vascular dysfunction associated with diabetes and other cardiovascular disease states. Acute L-arginine supplementation can prevent or reverse EC dysfunction and restore EC-dependent vasodilation in diabetes (1, 31). Reduced availability of L-arginine for NOS can occur via increased activity or expression of arginase, an enzyme that competes with NOS for L-arginine, producing ornithine and urea.Two isoforms of arginase exist in mammals, arginase I and II (AI and AII, respectively) (8, 23). AI, which is located in the cytoplasm, is expressed most abundantly in liver, whereas AII is a mitochondrial enzyme expressed primarily in the kidney. Both AI and AII have been found in EC populations (11, 34). During diabetes, impaired vascular function is closely associated with oxidative stress and inflammation (12, 28), both of which have been associated with elevated arginase activity and expression (4, 18).Enhanced arginase activity appears to be involved in conditions characterized by vascular endothelial dysfunction (VED), such as diabetes, pulmonary hypertension, ischemia-reperfusion, and aging (5,19,29,33, 42). Additionally, high chronic L-arginine intake can induce arginase expression/activity, thereby inducing vascular dysfunction (20,21,30,35). Competition between arginase and NOS for their common substrate, arginine, suggests a cause-and-effect relationship in which...

Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes Mellitus

“…Arginase activity is increased and contributes to endothelial dysfunction in the aortas of atherosclerotic mice. 6 It has been demonstrated that arginase I is of importance for vascular dysfunction in a rat model of type 1 diabetes 11,23 and that the arginase II isoform contributes to renal injury in mice with type 1 diabetes. 24 In the type 2 diabetic Goto-Kakizaki rat model, arginase II was upregulated in aorta and myocardium.…”

Role for high-glucose-induced proteinO-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis

“…In experimental DM animal models, aortic fibrosis is associated with increased arginase I and II protein levels and activity (29,30). Increases in arginase II activity are also linked to diabetic renal injury (26).…”

“…Arginase converts L-arginine to urea and ornithine. Decreased availability of L-arginine via increases in arginase activity can reduce nitric oxide levels leading to impaired vascular function as seen with DM (29,30). On the other hand, increases in ornithine levels lead to enhanced polyamine and proline production.…”

“…Both isoforms are observed in many cell types including fibroblasts and can be induced by proinflammatory cytokines (25). Arginase I is mainly cytoplasmic and II mitochondrial (29). Increases in arginase(s) activity correlate positively with the level of glycemic control and tissue fibrosis in DM patients (20,29,30).…”

“…Arginase I is mainly cytoplasmic and II mitochondrial (29). Increases in arginase(s) activity correlate positively with the level of glycemic control and tissue fibrosis in DM patients (20,29,30). The role of arginases in regulating CF collagen synthesis in the setting of DM is yet to be explored.…”