The Disparate Roles of Nox1 and Nox4 Derived Oxidative Stress in Diabetic Associated Atherosclerosis Development. — ASN Events
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The Disparate Roles of Nox1 and Nox4 Derived Oxidative Stress in Diabetic Associated Atherosclerosis Development. (#140)

Stephen P Gray 1 , Elyse Di Marco 1 , Patrick Page 2 , Cedric Szyndralewiez 2 , Freddy Heitz 2 , Mark E Cooper 1 , Rhian Touyz 3 , Kirsten Wingler 4 , Harald Schmidt 4 , Karin A Jandeleit-Dahm 1
  1. Baker IDI Heart & Diabetes, Melbourne, Vic, Australia
  2. Genkyotex SA, Geneva, Switzerland
  3. Ottawa Research Institute, Ottawa, Canada
  4. Department of Pharamacology, Faculty of Medicine, Health & Life Science, University of Maastricht, Maastricht, The Netherlands

Individuals diagnosed with diabetes have accelerated development of atherosclerosis; however the mechanisms are poorly understood.  Oxidative stress appears to play a significant role, specifically NADPH oxidase (Nox)-derived ROS, as vascular Noxs are upregulated in high glucose conditions. 

The aim of this study was to delineate the role of Nox-derived oxidative stress in the development of diabetes-related atherosclerosis. We used Nox isoform specific-ApoE double knockout (dKO) mice, Nox1-/yApoE-/- and Nox4-/-ApoE-/-, as well as pharmacological Nox inhibition in ApoE-/- mice. 

Mice were rendered diabetic by streptozotocin (55mg/kg/day for 5 days), with non-diabetic wildtype mice as controls.  The Nox1/Nox4 inhibitor, GKT137831 (GKT), was administered at a dose of 60mg/kg/day by gavage for 10 weeks.  Aortas were removed and cleaned for quantification of atherosclerotic plaque area and immunohistochemical analysis, or frozen for RT-PCR analysis.

Diabetic Nox1-/yApoE-/-mice had a 55% reduction in plaque area in comparison to Nox1-+/yApoE-/- diabetic mice.  There was no change in plaque area in diabetic Nox4-/-ApoE-/- mice compared to Nox4+/+ApoE-/- diabetic mice.  Administration of GKT to diabetic ApoE-/- animals resulted in a 64% reduction in plaque area in comparison to ApoE-/- diabetic mice not receiving GKT.  Furthermore, imunohistochemistry analysis of the vascular wall identified a significant decrease in macrophage infiltration and lipid peroxidation in the diabetic Nox1-/yApoE-/- compared to the Nox1+/+ApoE-/- diabetic mice, but not the Nox4-/-ApoE-/-mice.  Similar patterns were identified in GKT treated diabetic ApoE-/- mice. RT-PCR demonstrated a significant reduction in the gene expression of the markers for oxidative stress, inflammation and pro-fibrotic markers in mice.  

These data indicate that Nox1-derived ROS promote a pro-inflammatory and pro-fibrotic environment and may contribute to the enhanced development of atherosclerosis seen in diabetes. Inhibition of Nox, specifically Nox1, may provide a new therapeutic strategy in the treatment of diabetes-accelerated atherosclerosis.