The role of tetrahydrobiopterin in inflammation and cardiovascular disease

Eileen McNeill; Keith M. Channon

doi:10.1160/TH12-06-0424

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(05): 832-839
DOI: 10.1160/TH12-06-0424

Theme Issue Article

Schattauer GmbH

The role of tetrahydrobiopterin in inflammation and cardiovascular disease

Authors

Eileen McNeill

¹Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

²Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
Keith M. Channon

¹Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

²Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

Abstract

Summary

The cofactor tetrahydrobiopterin (BH4) is required for nitric oxide (NO) production by all nitric oxide synthase (NOS) enzymes and is a key regulator of cellular redox signalling. When BH4 levels become limiting NOS enzymes become ‘uncoupled’ and produce superoxide rather than NO. Endothelial cell BH4 is required for the maintenance of vascular function through NO production, and reduced BH4 levels are associated with vascular dysfunction. Evidence increasingly points to important roles for BH4 and NOS enzymes in other vascular cell types. Leukocytes have a fundamental role in atherosclerosis, and new evidence points to a role in the control of hypertension. Leukocytes are a major site of iNOS expression, and the regulation of this isoform is another mechanism by which BH4 availability may modulate disease. This review provides an overview of BH4 control of NOS function in both endothelial cells and leukocytes in the context of vascular disease and current therapeutic evaluations.

Keywords

Tetrahydrobiopterin - BH4 - vascular disease - reactive oxygen species (ROS) - nitric oxide

Full Text

References

References
1 Alp NJ, Channon KM. Regulation of endothelial nitric oxide synthase by tetrahydrobiopterin in vascular disease. Arterioscler Thromb Vasc Biol 2004; 24: 413-420.
2 Stuehr DJ. Mammalian nitric oxide synthases. Biochim Biophys Acta 1999; 1411: 217-230.
3 Crabtree MJ, Channon KM. Synthesis and recycling of tetrahydrobiopterin in endothelial function and vascular disease. Nitric Oxide 2011; 25: 81-88.
4 Vasquez-Vivar J. et al. Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors. Proc Natl Acad Sci USA 1998; 95: 9220-9225.
5 Crabtree MJ. et al. Quantitative regulation of intracellular endothelial nitric oxide synthase (eNOS) coupling by both tetrahydrobiopterin-eNOS stoichiometry and biopterin redox status: Insights from cells with tet-regulated GTP cyclohydrolase I expression. J Biol Chem 2009; 284: 1136-1144.
6 Werner-Felmayer G. et al. Tetrahydrobiopterin biosynthesis, utilization and pharmacological effects. Curr Drug Metab 2002; 3: 159-173.
7 Tatham AL. et al. GTP cyclohydrolase I expression, protein, and activity determine intracellular tetrahydrobiopterin levels, independent of GTP cyclohydrolase feedback regulatory protein expression. J Biol Chem 2009; 284: 13660-13668.
8 Alp NJ. et al. Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression. J Clin Invest 2003; 112: 725-735.
9 Alp NJ. 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; 24: 445-450.
10 Khoo JP. et al. A pivotal role for tetrahydrobiopterin in pulmonary hypertension. Circulation 2005; 111: 2126-2133.
11 Bendall JK. et al. Stoichiometric relationships between endothelial tetrahydrobiopterin, eNOS activity and eNOS coupling in vivo: Insights from transgenic mice with endothelial-targeted GTPCH and eNOS over-expression. Circ Res 2005; 97: 864-871.
12 Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells can transduce an atheroprotective force. Arterioscler Thromb Vasc Biol 1998; 18: 677-685.
13 Widder JD. et al. Regulation of Tetrahydrobiopterin Biosynthesis by Shear Stress. Circ Res 2007; 108: 830-838.
14 Wilcox JN. et al. Expression of multiple isoforms of nitric oxide synthase in normal and atherosclerotic vessels. Arterioscler Thromb Vasc Biol 1997; 17: 2479-2488.
15 Cosentino F. et al. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 1997; 96: 25-28.
16 Bouloumie A. et al. Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production. Hypertension 1997; 30: 934-941.
17 Katusic ZS. et al. Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 1998; 18: 27-32.
18 Shimizu S. et al. Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction of GTP-cyclohydrolase I and increases nitric oxide synthase activity in vascular endothelial cells. Free Radic Biol Med 2003; 34: 1343-1352.
19 Huang A. et al. Cytokine-stimulated GTP cyclohydrolase I expression in endothelial cells requires coordinated activation of nuclear factor-kappaB and Stat1/Stat3. Circ Res 2005; 96: 164-171.
20 Gross SS, Levi R. Tetrahydrobiopterin synthesis: an absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle. J Biol Chem 1992; 267: 25722-25729.
21 Sakai N. et al. Tetrahydrobiopterin is required for cytokine-induced nitric oxide production in a murine macrophage cell line (RAW 264). Mol Pharmacol 1993; 43: 6-10.
22 Chen W. et al. Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation. J Biol Chem 2011; 286: 13846-13851.
23 Milstien S. et al. Purification and cloning of the GTP cyclohydrolase I feedback regulatory protein. GFR J Biol Chem 1996; 271: 19743-19751.
24 Curtius HC. et al. Tetrahydrobiopterin biosynthesis. Studies with specifically labeled (2H)NAD(P)H and 2H2O and of the enzymes involved. Eur J Biochem 1985; 148: 413-419.
25 Franscini N. et al. Critical role of interleukin-1beta for transcriptional regulation of endothelial 6-pyruvoyltetrahydropterin synthase. Arterioscler Thromb Vasc Biol 2003; 23: e50-e53.
26 Werner ER. et al. Bacterial lipopolysaccharide down-regulates expression of GTP cyclohydrolase I feedback regulatory protein. J Biol Chem 2002; 277: 10129-10133.
27 Nagatsu T. et al. Udenfriend, Conversion of L-tyrosine to 3,4-dihydroxyphenylalanine by cell-free preparations of brain and sympathetically innervated tissues. Biochem Biophys Res Commun 1964; 14: 543-549.
28 Kaufman S. The Structure of the Phenylalanine-Hydroxylation Cofactor. Proc Natl Acad Sci USA 1963; 50: 1085-1093.
29 Chowdhary S, Townend JN. Role of nitric oxide in the regulation of cardiovascular autonomic control. Clin Sci 1999; 97: 5-17.
30 Fortin CF. et al. Sepsis, leukocytes, and nitric oxide (NO): an intricate affair. Shock 2010; 33: 344-352.
31 Ignarro LJ. Nitric oxide as a unique signaling molecule in the vascular system: a historical overview. J Physiol Pharmacol 2002; 53: 503-514.
32 Aicher A. et al. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 2003; 9: 1370-1376.
33 Landmesser U. et al. Statin-induced improvement of endothelial progenitor cell mobilization, myocardial neovascularization, left ventricular function, and survival after experimental myocardial infarction requires endothelial nitric oxide synthase. Circulation 2004; 110: 1933-1939.
34 Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res 2000; 87: 840-844.
35 Hill JM. et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 2003; 348: 593-600.
36 Liu VW, Huang PL. Cardiovascular roles of nitric oxide: a review of insights from nitric oxide synthase gene disrupted mice. Cardiovasc Res 2008; 77: 19-29.
37 Huang PL. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995; 377: 239-242.
38 Moroi M. et al. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Invest 1998; 101: 1225-1232.
39 Chen J. et al. Hypertension does not account for the accelerated atherosclerosis and development of aneurysms in male apolipoprotein e/endothelial nitric oxide synthase double knockout mice. Circulation 2001; 104: 2391-2394.
40 Kuhlencordt PJ. et al. Accelerated atherosclerosis, aortic aneurysm formation, and ischemic heart disease in apolipoprotein E/endothelial nitric oxide synthase double-knockout mice. Circulation 2001; 104: 448-454.
41 Ponnuswamy P. et al. eNOS protects from atherosclerosis despite relevant superoxide production by the enzyme in apoE mice. PloS one 2012; 7: e30193.
42 Schulz E. et al. Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation 2002; 105: 1170-1175.
43 Ozaki M. et al. Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. J Clin Invest 2002; 110: 331-340.
44 Schmidt TS. et al. Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in apolipoprotein E-knockout mice. Clin Sci 2010; 119: 131-142.
45 Hattori Y. et al. Oral administration of tetrahydrobiopterin slows the progression of atherosclerosis in apolipoprotein E-knockout mice. Arterioscler Thromb Vasc Biol 2007; 27: 865-870.
46 Cosentino F, Katusic ZS. Tetrahydrobiopterin and dysfunction of endothelial nitric oxide synthase in coronary arteries. Circulation 1995; 91: 139-144.
47 McNeill E. et al. Greaves, Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications. Clinical Sci 2010; 118: 641-655.
48 Weber C. et al. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol 2008; 8: 802-815.
49 Libby P. et al. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-1143.
50 Nakashima Y. et al. Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 1998; 18: 842-851.
51 Guzik TJ. et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Ex Med 2007; 204: 2449-2460.
52 Wenzel P. et al. Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation 2011; 124: 1370-1381.
53 Harrison DG. et al. Inflammation, immunity, and hypertension. Hypertension 2011; 57: 132-140.
54 MacMicking JD. et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995; 81: 641-650.
55 Cobb JP. et al. Inducible nitric oxide synthase (iNOS) gene deficiency increases the mortality of sepsis in mice. Surgery 1999; 126: 438-442.
56 Luoma JS, Yla-Herttuala S. Expression of inducible nitric oxide synthase in macrophages and smooth muscle cells in various types of human atherosclerotic lesions. Virchows Arch 1999; 434: 561-568.
57 Cromheeke KM. et al. Inducible nitric oxide synthase colocalizes with signs of lipid oxidation/peroxidation in human atherosclerotic plaques. Cardiovasc Res 1999; 43: 744-754.
58 Detmers PA. et al. Deficiency in inducible nitric oxide synthase results in reduced atherosclerosis in apolipoprotein E-deficient mice. J Immunol 2000; 165: 3430-3435.
59 Kuhlencordt PJ. et al. Genetic deficiency of inducible nitric oxide synthase reduces atherosclerosis and lowers plasma lipid peroxides in apolipoprotein E-knockout mice. Circulation 2001; 103: 3099-3104.
60 Chen J. et al. Effects of chronic treatment with L-arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase double-knockout mice. Arterioscler Thromb Vasc Biol 2003; 23: 97-103.
61 Miyoshi T. et al. Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice. Life Sci 2006; 79: 525-531.
62 Ponnuswamy P. et al. Oxidative stress and compartment of gene expression determine proatherosclerotic effects of inducible nitric oxide synthase. Am J Pathol 2009; 174: 2400-2410.
63 Hattori Y. et al. Tetrahydrobiopterin and GTP cyclohydrolase I in a rat model of endotoxic shock: relation to nitric oxide synthesis. Exp Physiol 1996; 81: 665-671.
64 Upmacis RK. et al. Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase. Am J Physiol Heart Circ Physiol 2007; 293: H2878-H2887.
65 Sun J. et al. Reactive oxygen and nitrogen species regulate inducible nitric oxide synthase function shifting the balance of nitric oxide and superoxide production. Arch Biochem Biophys 2010; 494: 130-137.
66 Xia Y. et al. Inducible nitric-oxide synthase generates superoxide from the reductase domain. J Biol Chem 1998; 273: 22635-22639.
67 Linares E. et al. Role of peroxynitrite in macrophage microbicidal mechanisms in vivo revealed by protein nitration and hydroxylation. Free Radic Biol Med 2001; 30: 1234-1242.
68 Huisman A. et al. Anti-inflammatory effects of tetrahydrobiopterin on early rejection in renal allografts: modulation of inducible nitric oxide synthase. FASEB J 2002; 16: 1135-1137.
69 Antoniades C. et al. Altered plasma versus vascular biopterins in human atherosclerosis reveal relationships between endothelial nitric oxide synthase coupling, endothelial function, and inflammation. Circulation 2007; 116: 2851-2859.
70 Antoniades C. et al. Induction of vascular GTP-cyclohydrolase I and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis. Circulation 2011; 124: 1860-1870.
71 Antoniades C. et al. GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. J Am Coll Cardiol 2008; 52: 158-165.
72 Heitzer T. et al. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with Type II diabetes mellitus. Diabetologia 2000; 43: 1435-1438.
73 Higashi Y. et al. Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals. Am J Hypertens 2002; 15: 326-332.
74 Stroes E. et al. Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. J Clin Invest 1997; 99: 41-46.
75 Heitzer T. et al. Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase. Circ Res 2000; 86: E36-E41.
76 Maier W. et al. Tetrahydrobiopterin improves endothelial function in patients with coronary artery disease. J Cardiovasc Pharmacol 2000; 35: 173-178.
77 Cosentino F. et al. Chronic treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolaemia. Heart 2008; 94: 487-492.
78 Cunnington C. et al. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease. Circulation 2012; 125: 1356-1366.
79 Cunnington C, Channon KM. Tetrahydrobiopterin: pleiotropic roles in cardiovascular pathophysiology. Heart 2010; 96: 1872-1877.
80 Leitner KL. et al. Low tetrahydrobiopterin biosynthetic capacity of human monocytes is caused by exon skipping in 6-pyruvoyl tetrahydropterin synthase. Biochem J 2003; 373: 681-688.