Abstract
Objective: NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout ( Apoe -/- ) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4. Methods: Six-week-old male Apoe -/- mice, eET-1/ Apoe -/- and eET-1/ Apoe -/- mice deficient in Nox1 (eET-1/ Apoe -/- / Nox1 y/- ) or Nox4 (eET-1/ Apoe -/- / Nox4 -/- ) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP injections for 5 days and studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Plasma cholesterol, HDL and triglycerides were measured. Results: Diabetic Apoe -/- mice presented an impaired endothelium-dependent vasodilatory response to acetylcholine, which was not observed in diabetic eET-1/ Apoe -/- , eET-1/ Apoe -/- / Nox1 y/- or eET-1/ Apoe -/- / Nox4 -/- mice (E max : 20±6 vs 99±1, 98±1 and 100±0%). ET-1 overexpression caused a 1.8-fold increase in MA media/lumen of diabetic Apoe -/- mice (5.3±0.3 vs 2.9±0.2%), which was further increased 1.2-fold by Nox4 (6.4±0.3%) but not Nox1 knockout (5.5±0.3%). ET-1 overexpression exaggerated >2-fold the atherosclerotic lesion area in the aortic sinus in diabetic Apoe -/- mice (plaque area [x10 5 μm 2 ]: 5.3±0.5 vs 2.9±0.6), which was reduced ~40% by Nox1 and Nox4 knockout (plaque area [x10 5 μm 2 ]: 3.3±0.6 and 3.6±0.6). Plasma triglycerides were unaffected by ET-1 overexpression but reduced by Nox1 (2.2±0.4 vs 3.4±0.3 mmol/L) and Nox4 knockout (1.8±0.4 mmol/L). Plasma HDL and cholesterol were similar between groups. Conclusions: Increased levels of ET-1 exaggerate diabetes-accelerated atherosclerosis through NOX1 and NOX4, despite paradoxically improving endothelium-dependent relaxation in small arteries.
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