Tetrahydrobiopterin Deficiency and Nitric Oxide Synthase Uncoupling Contribute to Atherosclerosis Induced by Disturbed Flow
Objective—Tetrahydrobiopterin (BH4) is a critical cofactor for nitric oxide (NO) synthesis by NO synthase (NOS). Recently, we demonstrated that disturbed flow produced by partial carotid ligation decreases BH4 levels in vivo. We therefore aimed to determine whether atherosclerosis induced by disturbed flow is due to BH4 deficiency and NOS uncoupling and whether increasing BH4 would prevent endothelial dysfunction, plaque inflammation, and atherosclerosis.
Methods and Results—We produced a region of disturbed flow in apolipoprotein E−/− mice using partial carotid ligation and fed these animals a high-fat diet. This caused endothelial NOS uncoupling as characterized by increased vascular superoxide production, altered vascular reactivity, and a change in endothelial NOS migration on low-temperature gel. These perturbations were accompanied by severe atherosclerosis, infiltration of T cells and macrophages, and an increase in cytokine production. Treatment with BH4 recoupled NOS, decreased superoxide production, improved endothelium-dependent vasodilatation, and virtually eliminated atherosclerosis. BH4 treatment also markedly reduced vascular inflammation and improved the cytokine milieu induced by disturbed flow.
Conclusion—Our results highlight a key role of BH4 deficiency and NOS uncoupling in atherosclerosis induced by disturbed flow and provide insight into the effect of modulating vascular BH4 levels on atherosclerosis and inflammation at these sites of the circulation.
- Received December 27, 2010.
- Accepted April 1, 2011.
- © 2011 American Heart Association, Inc.