Abstract 16417: Bone Marrow Transplants From NOX2-Deficient Mice To WT Mice Protect Against Diabetes-Induced Vascular Endothelial Dysfunction Through Decreased Arginase Activity
Increased arginase activity has been implicated in diabetes-induced vascular dysfunction by reducing L-arginine bioavailability and nitric oxide production. Our lab previously reported that inhibiting NADPH oxidase blocks oxidative stress induced increases in arginase activity. Furthermore, the NADPH oxidase NOX2 isoform has been reported to be a major contributing factor in vascular endothelial dysfunction (VED). We hypothesized that NOX2 activity in bone marrow derived cells plays a key role in diabetes-induced VED via increasing arginase activity. We tested this concept using wild type (WT) mice transplanted with bone marrow (BMT) from NOX2-deficient mice (NOX2 to WT) or WT mice (WT to WT). Four weeks after the transplants, the mice were rendered diabetic with streptozotocin. Genotypes of blood cells, aorta and tail tissues from recipients were determined by RT-PCR. Vascular endothelial function was assessed by measuring vasorelaxation in aortic rings (N = 4-6) in response to acetylcholine. PCR studies confirmed that only leukocytes in the NOX2 to WT mice were NOX2 negative. Vascular function studies show that WT to WT diabetic mice had a marked reduction of maximum endothelium-dependent vasorelaxation (by 61.3%, p<0.001) compared to the WT to WT control mice. This impaired vasorelaxation was improved in NOX2 to WT diabetic mice (by 52.0%, p<0.001). Incubation of aortic rings with an arginase inhibitor (ABH, 100 μM, 1hr) improved maximal vasorelaxation in WT to WT diabetic mice, but not in the NOX2 to WT diabetic mice. Elevation of vascular arginase activity was completely blocked in the NOX2 to WT diabetic mice. We conclude that NOX2 gene expression in bone marrow derived cells plays a prominent role in diabetes-induced increase in arginase activity and the resulting vascular endothelial dysfunction.
- © 2011 by American Heart Association, Inc.