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, which are upregulated in activity by glucose. There are three principal isoforms of Nox in the vasculature, Nox1, 2 and 4. We have previously demonstrated a role for Nox1 in the development of atherosclerosis in a short-term diabetic model. However, at present the role of the Nox4 isoform is contentious, with some studies suggesting a vasculoprotective role, with others suggesting Nox4 plays a pathogenic role. To date, no study has investigated the role of Nox4 in the development of atherosclerosis in a long-term diabetic model.
The aim of this present study was to examine the role of Nox4 deletion in an advanced model of diabetes associated atherosclerosis.
Nox4-/-ApoE-/- mice, in addition to Nox4+/+ApoE-/- were rendered diabetic by streptozotocin (55mg/kg/day for 5 days), with non-diabetic mice serving as controls. Mice were followed for a duration of 20 weeks, at which point they were culled for analysis.
After 20 weeks of diabetes, deletion of the Nox4 isoform resulted in a 65% increase in atherosclerosis development compared to Nox4+/+ApoE-/- diabetic mice. Furthermore, diabetic Nox4-/-ApoE-/- had a significant increase in the expression of aortic pro-oxidative markers, both at the gene and protein level. In addition, to increased expression of superoxide dependant pro-inflammatory pathways, such as MCP-1. Examination of pro-fibrotic markers identified a greater accumulation of collagen fibres (collagen I and III) within the vascular wall and plaque.
Deletion of Nox4 in diabetes accelerates the development of atherosclerosis. This acceleration appears to be mediated through increased oxidative stress and aortic accumulation of peroxynitrite. In addition to increased expression of pro-inflammatory and pro-fibrotic pathways. These studies indicated a potential vasculo-protective role for Nox4 in cardiovascular function, particularly in diabetes.