title: Tetrahydrobiopterin deficiency and nitric oxide synthase uncoupling contribute to atherosclerosis induced by disturbed flow.
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.
  
  
  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 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.
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Amir
authors.initials: A
authors.lastname: Rezvan
authors.forename: Hanjoong
authors.initials: H
authors.lastname: Jo
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000172:deficiency; D017536:Carotid Artery, Common / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology / Q000601:surgery; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology / Q000276:immunology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008026:Ligation; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012039:Regional Blood Flow; D013481:Superoxides / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D018836:Inflammation Mediators; D014665:Vasodilator Agents; D013481:Superoxides; D001708:Biopterins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C003402:sapropterin