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OS 21-01 NOX1 OR NOX4 DELETION PREVENTS TYPE 1 DIABETES-INDUCED ENDOTHELIAL DYSFUNCTION.

OBJECTIVE
The prognosis of type-1 diabetes remains poor and is primarily related to the increased risk of vascular complications. 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 microangiopathy 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.


DESIGN AND METHOD
Diabetes-related vascular injury were studied in atherosclerosis-prone apolipoprotein knockout (Apoe) mice. Six-week-old male Apoe mice, Apoe mice deficient in Nox1 (Apoe/Nox1) and Nox4 (Apoe/Nox4) were rendered diabetic by streptozotocin treatment (STZ, 55 mg/kg/day, ip) for 5 days. 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 to acetylcholine of only 46%, which was further decreased by ∼50% by diabetes. In contrast, endothelium-dependent relaxations to acetylcholine were 1.5-fold higher in diabetic Apoe/Nox1 and Apoe/Nox4 mice compared to vehicle-treated Apoe mice. Endothelium-independent relaxation responses to the nitric oxide donor, sodium nitroprusside, were similar in all groups. Diabetes decreased MA stiffness in Apoe mice, as indicated by a rightward displacement of the stress-strain curves, which was blunted by Nox1 or Nox4 knockout. MA media/lumen was unaltered by diabetes. Knockout of Nox4 but not Nox1 increased MA media/lumen 1.4-fold in diabetic Apoe mice.


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 also seems to have dual actions on the vasculature, as it is also protective against vascular remodeling of small arteries in type 1 diabetes.