Tetrahydrobiopterin deficiency and nitric oxide synthase uncoupling contribute to atherosclerosis induced by disturbed flow.
Arterioscler Thromb Vasc Biol
; 31(7): 1547-54, 2011 Jul.
Article
em En
| MEDLINE
| ID: mdl-21512164
ABSTRACT
OBJECTIVE:
Tetrahydrobiopterin (BH(4)) 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 BH(4) levels in vivo. We therefore aimed to determine whether atherosclerosis induced by disturbed flow is due to BH(4) deficiency and NOS uncoupling and whether increasing BH(4) would prevent endothelial dysfunction, plaque inflammation, and atherosclerosis. METHODS ANDRESULTS:
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 BH(4) recoupled NOS, decreased superoxide production, improved endothelium-dependent vasodilatation, and virtually eliminated atherosclerosis. BH(4) treatment also markedly reduced vascular inflammation and improved the cytokine milieu induced by disturbed flow.CONCLUSIONS:
Our results highlight a key role of BH(4) deficiency and NOS uncoupling in atherosclerosis induced by disturbed flow and provide insight into the effect of modulating vascular BH(4) levels on atherosclerosis and inflammation at these sites of the circulation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vasodilatação
/
Biopterinas
/
Endotélio Vascular
/
Artéria Carótida Primitiva
/
Aterosclerose
/
Óxido Nítrico Sintase Tipo III
/
Inflamação
Tipo de estudo:
Etiology_studies
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos