Therapeutic Potential of Tetrahydrobiopterin for Treating Vascular and Cardiac Disease

Tetrahydrobiopterin is the reduced unconjugated pterin that serves as an essential cofactor for the normal enzymatic function of the aromatic amino acid hydroxylases and for the nitric oxide synthases (NOS). Its role in the latter biochemistry is being increasing appreciated, as depletion or oxidation of BH4 results in a condition of NOS uncoupling, resulting in a nitroso-oxidative imbalance. Recent experimental studies support an important pathophysiologic role of BH4 deficiency as well as the therapeutic potential of BH4 repletion for hypertension, endothelial dysfunction, atherosclerosis, diabetes, cardiac hypertrophic remodeling, and heart failure. In addition to BH4, studies are also examining the potential role of folic acid therapy, because folic acid can enhance BH4 levels and the NOS coupling state. This review summarizes these recent studies focusing on the biochemistry and pharmacology of BH4 and its potential role for treating cardiovascular disease.

[1]  A. Chakrapani,et al.  Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomised placebo-controlled study , 2007, The Lancet.

[2]  H. Satoh,et al.  Oral Administration of Tetrahydrobiopterin Slows the Progression of Atherosclerosis in Apolipoprotein E-Knockout Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[3]  P. Galuppo,et al.  Endothelial Nitric Oxide Synthase Uncoupling Impairs Endothelial Progenitor Cell Mobilization and Function in Diabetes , 2007, Diabetes.

[4]  D. Kass,et al.  Role of oxidative stress in cardiac hypertrophy and remodeling. , 2007, Hypertension.

[5]  K. Reynolds,et al.  Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. , 2006, JAMA.

[6]  D. Kass,et al.  Tetrahydrobiopterin and Cardiovascular Disease , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[7]  S. Neubauer,et al.  5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels: Effects on Vascular Tetrahydrobiopterin Availability and Endothelial Nitric Oxide Synthase Coupling , 2006, Circulation.

[8]  M. Carrier,et al.  Effect of tetrahydrobiopterin on selective endothelial dysfunction of epicardial porcine coronary arteries induced by cardiopulmonary bypass. , 2006, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[9]  Z. Yousefipour,et al.  Oxidative Stress-Associated Vascular Aging Is Xanthine Oxidase-Dependent but not NAD(P)H Oxidase-Dependent , 2006, Journal of cardiovascular pharmacology.

[10]  U. Förstermann,et al.  Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace , 2006, Circulation.

[11]  D. Kass,et al.  L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. , 2006, JAMA.

[12]  T. Rabelink,et al.  Tetrahydrobiopterin, but Not l-Arginine, Decreases NO Synthase Uncoupling in Cells Expressing High Levels of Endothelial NO Synthase , 2006, Hypertension.

[13]  T. Münzel,et al.  Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[14]  T. Gori,et al.  Folic Acid Does Not Limit Endothelial Dysfunction Induced by Ischemia and Reperfusion: A Human Study , 2005, Journal of cardiovascular pharmacology.

[15]  B. Crane,et al.  Structure of a loose dimer: an intermediate in nitric oxide synthase assembly. , 2005, Journal of molecular biology.

[16]  N. Alp,et al.  Endothelial nitric oxide synthase dysfunction in diabetic mice: importance of tetrahydrobiopterin in eNOS dimerisation , 2005, Diabetologia.

[17]  Y. Hattori,et al.  Supplementation with tetrahydrobiopterin prevents the cardiovascular effects of angiotensin II-induced oxidative and nitrosative stress , 2005, Journal of hypertension.

[18]  Kenichi Watanabe,et al.  Different effects of a high-cholesterol diet on ischemic cardiac dysfunction and remodeling induced by coronary stenosis and coronary occlusion. , 2005, Journal of the American College of Cardiology.

[19]  N. Alpert,et al.  High-dose folic acid acutely improves coronary vasodilator function in patients with coronary artery disease. , 2005, Journal of the American College of Cardiology.

[20]  D. Kass,et al.  Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. , 2005, The Journal of clinical investigation.

[21]  K. Rockett,et al.  Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension , 2005, Circulation.

[22]  K. Channon,et al.  Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells. , 2005, Cardiovascular research.

[23]  Å. Sjöholm,et al.  Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease. , 2004, American journal of physiology. Endocrinology and metabolism.

[24]  N. Alp,et al.  Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[25]  N. Alp,et al.  Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[26]  J. Whitworth,et al.  Role of Tetrahydrobiopterin in Adrenocorticotropic Hormone‐Induced Hypertension in the Rat , 2004, Clinical and experimental hypertension.

[27]  E. Werner,et al.  In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide , 1995, Naunyn-Schmiedeberg's Archives of Pharmacology.

[28]  S. Kaufman.  Some metabolic relationships between biopterin and folate: Implications for the “methyl trap hypothesis” , 1991, Neurochemical Research.

[29]  H. Hasegawa,et al.  Tetrahydrobiopterin uptake in supplemental administration: elevation of tissue tetrahydrobiopterin in mice following uptake of the exogenously oxidized product 7,8-dihydrobiopterin and subsequent reduction by an anti-folate-sensitive process. , 2004, Journal of pharmacological sciences.

[30]  N. Blau,et al.  Plasma tetrahydrobiopterin and its pharmacokinetic following oral administration. , 2004, Molecular genetics and metabolism.

[31]  K. Griendling,et al.  Reactive oxygen species in the vasculature: molecular and cellular mechanisms. , 2003, Hypertension.

[32]  D. Harrison,et al.  Interactions of Peroxynitrite, Tetrahydrobiopterin, Ascorbic Acid, and Thiols , 2003, Journal of Biological Chemistry.

[33]  E. Podjarny,et al.  Effect of Tetrahydrobiopterin on Blood Pressure in Rats after Subtotal Nephrectomy , 2003, Nephron Physiology.

[34]  Steven M Holland,et al.  Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. , 2003, The Journal of clinical investigation.

[35]  Y. Hattori,et al.  HMG-CoA Reductase Inhibitor Increases GTP Cyclohydrolase I mRNA and Tetrahydrobiopterin in Vascular Endothelial Cells , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[36]  B. Kalyanaraman,et al.  The Role of Tetrahydrobiopterin in Superoxide Generation from eNOS: Enzymology and Physiological Implications , 2003, Free radical research.

[37]  K. Noguchi,et al.  Beneficial effect of tetrahydrobiopterin on ischemia-reperfusion injury in isolated perfused rat hearts. , 2002, The Journal of thoracic and cardiovascular surgery.

[38]  Zhi‐qiang Wang,et al.  Why do nitric oxide synthases use tetrahydrobiopterin? , 2002, Journal of inorganic biochemistry.

[39]  Tomoya Yamashita,et al.  Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apoE-deficient mice. , 2002, The Journal of clinical investigation.

[40]  S. Verma,et al.  Novel cardioprotective effects of tetrahydrobiopterin after anoxia and reoxygenation: Identifying cellular targets for pharmacologic manipulation. , 2002, The Journal of thoracic and cardiovascular surgery.

[41]  S. Verma,et al.  Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. , 2002, American journal of physiology. Heart and circulatory physiology.

[42]  K. Chayama,et al.  Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals. , 2002, American journal of hypertension.

[43]  B. Mayer,et al.  Tetrahydrobiopterin in nitric oxide synthesis: a novel biological role for pteridines. , 2002, Current drug metabolism.

[44]  R. Cohen,et al.  Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. , 2002, The Journal of clinical investigation.

[45]  M. Stratford,et al.  Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate. , 2002, Free radical biology & medicine.

[46]  A. Kashiwagi,et al.  Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress. , 2001, Journal of the American College of Cardiology.

[47]  B. Kalyanaraman,et al.  Reaction of tetrahydrobiopterin with superoxide: EPR-kinetic analysis and characterization of the pteridine radical. , 2001, Free radical biology & medicine.

[48]  T. Münzel,et al.  Mechanisms Underlying Endothelial Dysfunction in Diabetes Mellitus , 2001, Circulation research.

[49]  Qianqian Wang,et al.  Rapid Kinetic Studies Link Tetrahydrobiopterin Radical Formation to Heme-dioxy Reduction and Arginine Hydroxylation in Inducible Nitric-oxide Synthase* , 2001, The Journal of Biological Chemistry.

[50]  N. Blau,et al.  Systemic Tetrahydrobiopterin (BH4) Levels and Coronary Artery Disease , 2001, Cardiology.

[51]  H. Maegawa,et al.  Oral Administration of Tetrahydrobiopterin Prevents Endothelial Dysfunction and Vascular Oxidative Stress in the Aortas of Insulin-Resistant Rats , 2000, Circulation research.

[52]  E. Werner,et al.  Low-temperature optical absorption spectra suggest a redox role for tetrahydrobiopterin in both steps of nitric oxide synthase catalysis. , 2000, Biochemistry.

[53]  N. Bec,et al.  The role of tetrahydrobiopterin in the activation of oxygen by nitric-oxide synthase. , 2000, Journal of inorganic biochemistry.

[54]  T. Rabelink,et al.  Folic acid reverts dysfunction of endothelial nitric oxide synthase. , 2000, Circulation research.

[55]  N. Blau,et al.  Tetrahydrobiopterin biosynthesis, regeneration and functions. , 2000, The Biochemical journal.

[56]  N. Sigal,et al.  Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[57]  B. Mayer,et al.  Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase. , 2000, Circulation research.

[58]  篠崎 一哉.  Abnormal Biopterin Metabolism Is a Major Cause of Impaired Endothelium-Dependent Relaxation Through Nitric Oxide/O2[-] Imbalance in Insulin-Resistant Rat Aorta , 2000 .

[59]  H. Schmidt,et al.  Allosteric regulation of neuronal nitric oxide synthase by tetrahydrobiopterin and suppression of auto-damaging superoxide. , 2000, The Biochemical journal.

[60]  A. Kashiwagi,et al.  Abnormal biopterin metabolism is a major cause of impaired endothelium-dependent relaxation through nitric oxide/O2- imbalance in insulin-resistant rat aorta. , 1999, Diabetes.

[61]  D. Green,et al.  NITRIC OXIDE‐DEPENDENT ENDOTHELIAL FUNCTION IS UNAFFECTED BY ALLOPURINOL IN HYPERCHOLESTEROLAEMIC SUBJECTS , 1999, Clinical and experimental pharmacology & physiology.

[62]  H. Schmidt,et al.  Tetrahydrobiopterin Inhibits Monomerization and Is Consumed during Catalysis in Neuronal NO Synthase* , 1999, The Journal of Biological Chemistry.

[63]  J. Tainer,et al.  Mutational Analysis of the Tetrahydrobiopterin-binding Site in Inducible Nitric-oxide Synthase* , 1999, The Journal of Biological Chemistry.

[64]  P. Sun,et al.  Stoichiometric arginine binding in the oxygenase domain of inducible nitric oxide synthase requires a single molecule of tetrahydrobiopterin per dimer. , 1999, Biochemical and biophysical research communications.

[65]  P. Fitzpatrick,et al.  Tetrahydropterin-dependent amino acid hydroxylases. , 1999, Annual review of biochemistry.

[66]  K. Hirata,et al.  Hypotension and reduced nitric oxide-elicited vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. , 1998, The Journal of clinical investigation.

[67]  N. Bec,et al.  Reaction of Neuronal Nitric-oxide Synthase with Oxygen at Low Temperature , 1998, The Journal of Biological Chemistry.

[68]  E. Werner,et al.  Tetrahydrobiopterin alters superoxide and nitric oxide release in prehypertensive rats. , 1998, The Journal of clinical investigation.

[69]  D. Stuehr,et al.  Stopped-flow analysis of CO and NO binding to inducible nitric oxide synthase. , 1998, Biochemistry.

[70]  P. Ortiz de Montellano,et al.  Endothelial nitric oxide synthase: modulations of the distal heme site produced by progressive N-terminal deletions. , 1997, Biochemistry.

[71]  A. Quyyumi,et al.  Xanthine oxidase inhibition with oxypurinol improves endothelial vasodilator function in hypercholesterolemic but not in hypertensive patients. , 1997, Hypertension.

[72]  E. Werner,et al.  Characterization of bovine endothelial nitric oxide synthase as a homodimer with down-regulated uncoupled NADPH oxidase activity: tetrahydrobiopterin binding kinetics and role of haem in dimerization. , 1997, The Biochemical journal.

[73]  G. Pieper.  Acute amelioration of diabetic endothelial dysfunction with a derivative of the nitric oxide synthase cofactor, tetrahydrobiopterin. , 1997, Journal of cardiovascular pharmacology.

[74]  D. Stuehr.  Structure-function aspects in the nitric oxide synthases. , 1997, Annual review of pharmacology and toxicology.

[75]  J. Kastelein,et al.  Tetrahydrobiopterin restores endothelial function in hypercholesterolemia. , 1997, The Journal of clinical investigation.

[76]  E. Werner,et al.  Tetrahydrobiopterin-free neuronal nitric oxide synthase: evidence for two identical highly anticooperative pteridine binding sites. , 1996, Biochemistry.

[77]  H. S. Kim,et al.  Elevated blood pressures in mice lacking endothelial nitric oxide synthase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[78]  C. Tiefenbacher,et al.  Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. , 1996, Circulation.

[79]  D. Harrison,et al.  Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. , 1996, The Journal of clinical investigation.

[80]  M. Moskowitz,et al.  Hypertension in mice lacking the gene for endothelial nitric oxide synthase , 1995, Nature.

[81]  E. Werner,et al.  The pteridine binding site of brain nitric oxide synthase. Tetrahydrobiopterin binding kinetics, specificity, and allosteric interaction with the substrate domain. , 1994, The Journal of biological chemistry.

[82]  K. Baek,et al.  Macrophage nitric oxide synthase subunits. Purification, characterization, and role of prosthetic groups and substrate in regulating their association into a dimeric enzyme. , 1993, The Journal of biological chemistry.

[83]  P. Klatt,et al.  Multiple catalytic functions of brain nitric oxide synthase. Biochemical characterization, cofactor-requirement, and the role of N omega-hydroxy-L-arginine as an intermediate. , 1993, The Journal of biological chemistry.

[84]  D. Harrison,et al.  Hypercholesterolemia increases endothelial superoxide anion production. , 1993, The Journal of clinical investigation.

[85]  S. Snyder,et al.  Generation of superoxide by purified brain nitric oxide synthase. , 1992, The Journal of biological chemistry.

[86]  P. Klatt,et al.  Ca2+/calmodulin-dependent formation of hydrogen peroxide by brain nitric oxide synthase. , 1992, The Biochemical journal.

[87]  M. Marletta,et al.  Macrophage oxidation of L-arginine to nitric oxide, nitrite, and nitrate. Tetrahydrobiopterin is required as a cofactor. , 1989, The Journal of biological chemistry.

[88]  I. Study.  EPIDEMIOLOGY, CLINICAL FEATURES, AND PROGNOSTIC FACTORS OF PAEDIATRIC HIV INFECTION , 1988, The Lancet.

[89]  N. Holtzman,et al.  A disorder of biogenic amines in dihydropteridine reductase deficiency , 1978, Annals of neurology.

[90]  R. Cotton,et al.  TETRAHYDROBIOPTERIN TREATMENT OF VARIANT FORM OF PHENYLKETONURIA , 1975, The Lancet.

[91]  B. Clayton,et al.  NEW VARIANT OF PHENYLKETONURIA WITH PROGRESSIVE NEUROLOGICAL ILLNESS UNRESPONSIVE TO PHENYLALANINE RESTRICTION , 1975, The Lancet.

[92]  R. Cotton,et al.  Letter: Tetrahydrobiopterin treatment of variant form of phenylketonuria. , 1975, Lancet.

[93]  S. Kaufman.  Metabolism of the phenylalanine hydroxylation cofactor. , 1967, The Journal of biological chemistry.

[94]  S. Kaufman.  THE STRUCTURE OF THE PHENYLALANINE-HYDROXYLATION COFACTOR. , 1962, Proceedings of the National Academy of Sciences of the United States of America.