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Cited by 143Nitric Oxide and Endothelin EffectsCardiovascular Health and Disease PreventionAntioxidant Activity and Oxidative Stress

Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia

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Cosentino, F, Hürlimann, D, Delli Gatti, C, Chenevard, R, Blau, N, Alp, N J, Channon, K M, Eto, M +6 more·2008·Heart
DOI 10.1136/hrt.2007.122184
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Abstract

Background: Reduced availability of tetrahydrobiopterin (BH 4), an essential cofactor of nitric oxide (NO) synthase (NOS), decreases NO production and increases reactive oxygen species. Both mechanisms contribute to atherosclerotic vascular disease. Although acute supplementation of BH 4 improves endothelial dysfunction, the effect of chronic BH 4 in humans is unknown. Objective: To investigate the effect of chronic BH 4 supplementation on endothelial function and oxidative stress in hypercholesterolaemia. Design: Randomised double-blind, placebo-controlled trial. Setting: University Hospital. Patients: 22 hypercholesterolaemic patients (low-density lipoprotein (LDL) >4.5 mmol/l) were randomised to 4 weeks of oral BH 4 (400 mg twice daily) or placebo. Age-matched healthy volunteers served as controls. Main outcome measures: Endothelium-dependent and -independent vasodilatation was assessed by venous occlusion plethysmography. To elucidate the mechanisms of BH 4 effect, NO release and superoxide anion (O 2 −) production were measured in human aortic endothelial cells exposed to native LDL (2.6 mmol cholesterol/l). Results: BH 4 plasma levels were significantly increased by oral supplementation. NO-mediated vasodilatation to acetylcholine was reduced in patients compared with controls and restored by BH 4. No effect of BH 4 on endothelium-independent vasodilatation was seen. Furthermore, 8-F 2 isoprostane plasma levels, a marker of vascular oxidative stress, were reduced by BH 4. In LDL-treated endothelial cells, BH 4 levels and NO release were reduced and O 2 − production increased compared with control cells. Exogenous BH 4 normalised NO and O 2 − production. Conclusions: In hypercholesterolaemia, endothelial dysfunction and oxidative stress can be reversed by chronic oral treatment with BH 4. Thus, BH 4 availability is essential for maintaining NO synthesis and low O 2 − production by endothelial NOS in vivo, and may provide a rational therapeutic approach to prevent cardiovascular disease.

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Authors
Cosentino, F., Hürlimann, D., Delli Gatti, C., Chenevard, R., Blau, N., Alp, N. J., Channon, K. M., Eto, M., Lerch, P., Enseleit, F., Ruschitzka, F., Volpe, M., Lüscher, T. F., & Noll, G.
Affiliations
  • University Hospital Zurich (CH)
  • University Children's Hospital Zurich (CH)
  • University of Oxford (GB)
  • CSL (Switzerland) (CH)
  • Sapienza University of Rome (IT)
Corresponding author
Noll, G
ORCID
Venue
Heart
Publisher
BMJ
Published
2007-10-04
Volume
94
Issue
4
Pages
487-492
ISSN
  • 1355-6037 (ISSN-L)
  • 1468-201X
DOI
10.1136/hrt.2007.122184
OpenAlex
W2024848503
Cited by
143
References
28
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 11 · 2019: 4 · 2018: 12 · 2017: 4 · 2016: 8 · 2015: 5 · 2014: 13 · 2013: 6 · 2012: 12
FWCI
6.68
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Heart (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
British Heart Foundation (RG/07/003/23133)
Topics
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
  • Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
Keywords
tetrahydrobiopterin, hypercholesterolemia, endothelial dysfunction, oxidative stress, nitric oxide, nitric oxide synthase, superoxide, endothelium-dependent vasodilatation, LDL cholesterol, 8-isoprostane, atherosclerosis, oral supplementation
MeSH terms
Administration, Oral, Adult, Aged, Biopterins, Cells, Cultured, Double-Blind Method, Drug Administration Schedule, Endothelium, Vascular, Female, Forearm, Humans, Hypercholesterolemia, Cholesterol, LDL, Male, Middle Aged, Nitric Oxide, Plethysmography, Regional Blood Flow, Superoxides, Vasodilation, Oxidative Stress

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