Nox1 Plays a Key Role in Diabetes Accelerated Atherosclerosis
Background—In diabetes mellitus, vascular complications such as atherosclerosis are a major cause of death. The key underlying pathomechanisms are unclear. However, hyperglycemic oxidative stress appears to play a role with NADPH oxidase (Nox), the only known dedicated enzyme to generate ROS. Here we identify the Nox1 isoform as playing a key and pharmacologically targetable role in the accelerated development of diabetic atherosclerosis.
Methods and Results—Human aortic endothelial cells exposed to hyperglycemic conditions showed increased expression of Nox1, oxidative stress and proinflammatory markers in a Nox1-siRNA reversible manner. Similarly, the specific Nox inhibitor, GKT137831, prevented oxidative stress in response to hyperglycaemia in human aortic endothelial cells. To examine these observations in vivo, we investigated the role of Nox1 on plaque development in ApoE-/- mice 10 weeks after induction of diabetes. Deletion of Nox1, but not Nox4, had a profound anti-atherosclerotic effect correlating with reduced ROS formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration and reduced expression of pro-inflammatory and pro-fibrotic markers. Similarly, treatment of diabetic ApoE-/- mice with GKT137831 attenuated atherosclerosis development.
Conclusions—These studies identify a major pathological role for Nox1 and suggest that Nox1-dependent oxidative stress is a promising target for diabetic vasculopathies including atherosclerosis.
- Received July 20, 2012.
- Revision received February 16, 2013.
- Accepted March 6, 2013.