Abstract P225: Nox1 or Nox4 Deletion Prevents Type-1 Diabetes-induced Endothelial Dysfunction

Abstract

Objective: The prognosis of type-1 diabetes is in part related to the increased risk of vascular complications such as atherosclerosis. Overproduction of reactive oxygen species by NADPH oxidase (NOX) is believed to play an important role in diabetes-related vascular injury. NOX1 may play a role in the macrovascular disease, whereas NOX4 may have protective actions. Nevertheless, their role in diabetic vascular injury is less well understood. We hypothesized that deletion of Nox1 would prevent diabetes-induced endothelial dysfunction and vascular remodeling of small arteries whereas Nox4 would exaggerate vascular injury in atherosclerosis-prone apolipoprotein knockout ( Apoe -/- ) mice. Methods: Diabetes was induced by streptozotocin IP injections (STZ, 55 mg/kg/day) for 5 days in 6-week-old male Apoe -/- mice, Apoe -/- mice deficient in Nox1 ( Apoe -/- / Nox1 y/- ) and Nox4 ( Apoe -/- / Nox4 -/- ). Mice were studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Results: Apoe -/- mice presented a maximal endothelium-dependent vasodilatory response (E max ) to acetylcholine of 48±8%, which was further decreased by diabetes to 20±6%. In contrast, endothelium-dependent relaxations to acetylcholine were 1.5-fold higher in diabetic Apoe -/- / Nox1 y/- and Apoe -/- / Nox4 -/- mice compared to non-diabetic Apoe -/- mice (E max : 72±9 and 70±7 vs 48±8%). Diabetes decreased MA stiffness in Apoe -/- mice, as indicated by a rightward displacement of the stress-strain curves (strain at 140 mm Hg: 1.02±0.04 vs 0.75±0.04), which was blunted by Nox1 or Nox4 knockout (strain at 140 mm Hg: 0.77±0.02 and 0.81±0.02). MA media/lumen was unaltered by diabetes. Knockout of Nox4 but not Nox1 increased MA media/lumen 1.4-fold in diabetic Apoe -/- mice (4.1±0.4 and 3.5±0.2 vs 2.9±0.2%). Conclusions: These results suggest that NOX1 and NOX4 play a pathophysiological role in diabetes-induced endothelial dysfunction and contribute to potentially maladaptive changes in vascular stiffness. NOX4 seems to have dual actions on the vasculature, as it is also protective against vascular remodeling of small arteries in type 1 diabetes.