Tetrahydrobiopterin: Regulator of Endothelial Nitric Oxide Synthase 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)
- et al.
GTP cyclohydrolase I mRNA induction and tetrahydrobiopterin synthesis in human endothelial cells
Biochim Biophys Acta
(1997) - et al.
Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate
Free Radic Biol Med
(2002) - et al.
Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center
Cell
(1998) - et al.
Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease
Arterioscler Thromb Vasc Biol
(2004) - et al.
Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression
J Clin Invest
(2003) - et al.
Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in apoE-knockout mice
Arterioscler Thromb Vasc Biol
(2004) - et al.
GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerization
Cardiovasc Res
(2002) - et al.
Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice
Arterioscler Thromb Vasc Biol
(2001) - et al.
Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity
Circ Res
(2003) - et al.
Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase
Am J Physiol Regul Integr Comp Physiol
(2003)
Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase
Circulation
HMG-CoA reductase inhibitor increases GTP cyclohydrolase I mRNA and tetrahydrobiopterin in vascular endothelial cells
Arterioscler Thromb Vasc Biol
Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers: evidence for a dysfunctional nitric oxide synthase
Circ Res
Mechanisms underlying endothelial dysfunction in diabetes mellitus
Circ Res
Vascular endothelial dysfunction: does tetrahydrobiopterin play a role?
Am J Physiol Heart Circ Physiol
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