Tetrahydrobiopterin: Regulator of Endothelial Nitric Oxide Synthase in Vascular Disease

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In vascular disease states such as atherosclerosis and diabetes, endothelial nitric oxide (NO) bioactivity is reduced and oxidative stress is increased, resulting in endothelial dysfunction. Recent studies suggest that changes in the activity and regulation of endothelial NO synthase by its cofactor tetrahydrobiopterin (BH4) is an important contributor to endothelial dysfunction. Pharmacologic studies and more recent insights from genetically modified mouse models have improved the understanding of the mechanistic role and importance of BH4 in vascular disease pathogenesis. Targeting BH4 may provide new therapeutic strategies in vascular disease.

Section snippets

Regulation of Endothelial NOS

In common with all three NOS enzymes, endothelial NOS (NOS3) is a homodimeric oxidoreductase that catalyzes the production of NO from the guanidino nitrogen of L arginine, using molecular oxygen. The reductase domain of eNOS shares a close homology with the cytochrome P450 enzymes, generating electron flow from NADPH through the flavins FAD and FMN that are transferred to the oxidase domain of the other monomer where L-arginine oxidation occurs at the heme group in the active site (Figure 1A).

Vascular Disease: A Tetrahydrobiopterin Deficiency State?

The ability of BH4 to modulate both NO production and superoxide production in the endothelium has received considerable attention as a potential mechanism underlying endothelial dysfunction in vascular disease. Numerous studies have found that pharmacologic supplementation of BH4 augments NO-mediated effects in either cell culture or in vitro vessel rings or in animal models or patients with vascular disease risk factors (Alp and Channon, 2004, Katusic, 2001). However, more direct mechanistic

Endothelial NOS Uncoupling in Vascular Disease: Role of BH4

Several recent studies have sought to investigate the mechanisms relating BH4 availability to eNOS uncoupling in vascular disease using approaches other than pharmacologic BH4 supplementation.

In streptozotocin (STZ) diabetic rats, hyperglycemia resulted in endothelial dysfunction and increased vascular superoxide production. Increased vascular superoxide production was mediated by upregulation of NAD(P)H oxidases through a pathway in part dependent on protein kinase C (Hink et al. 2001).

Tetrahydrobiopterin As a Therapeutic Target

The importance of BH4 as a critical regulator of eNOS function suggests that BH4 may be a rational therapeutic target in vascular disease states. Indeed, several studies have already explored the effect of BH4 administration, either intravascular or oral, on endothelial functions. However, these studies have been limited to acute or short-term administration, used very high doses, and only determined the effects on endothelial-dependent relaxation rather than other variables related to vascular

Acknowledgments

Work in the author's laboratory is supported by grants from the British Heart Foundation and from The Wellcome Trust.

References (31)

  • TJ Guzik et al.

    Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase

    Circulation

    (2002)
  • Y Hattori et al.

    HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells

    Arterioscler Thromb Vasc Biol

    (2003)
  • T Heitzer et al.

    Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase

    Circ Res

    (2000)
  • U Hink et al.

    Mechanisms underlying endothelial dysfunction in diabetes mellitus

    Circ Res

    (2001)
  • ZS Katusic

    Vascular endothelial dysfunction: does tetrahydrobiopterin play a role?

    Am J Physiol Heart Circ Physiol

    (2001)
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      BH4 is necessary in blood vessels for the production of NO by the endothelial nitric oxide synthase (eNOS) [116]. A diminished BH4 level induces the degeneration of oxido-reduction steps accomplished by eNOS and causes increased synthesis of reactive oxygen species instead of nitric oxide with potential for deleterious effects on endothelial function [117]. An increase in endothelial BH4 notably improves vascular function in diabetes models [118].

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