It inhibits tetrahydrofolate reductase which recycles BH2 to BH4, leading to eNOS uncoupling and ROS production. We isolated peripheral blood mononuclear cells (PBMCs) derived from leucophoresis material of healthy volunteers or from whole blood of type 2 diabetic (n = 5, aged 70.6 ± 1.7 years) and nondiabetic (n = 5, aged 70.0 ± 2.9 years) patients, as described (11). Nevertheless, no association with the presence or extent of carotid atherosclerosis (assessed by carotid ultrasonography—intima-media thickness (IMT) and plaque) was found [159, 162]. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. In diabetic and obesity/insulin resistance states, the endothelial dysfunction is incremented promoting the development and progression of vascular diseases [].Endothelial dysfunction … Early ischaemic preconditioning requires Akt- and PKA-mediated activation of eNOS via serine1176 phosphorylation. In turn, increased ROS generation activates the Jun-N-terminal kinase (JNK) and JNK-dependent induction of tumor protein p53 (p53) and cyclin-dependent kinase inhibitor 1 (p21) resulting in decreased NF-κB activation. Synthesis of NO can be regulated at the endothelial nitric oxide synthase (eNOS) gene expression level and eNOS enzymatic activity level. Patt BT, Jarjoura D, Haddad DN, Sen CK, Roy S, Flavahan NA, Khayat RN. It is a consequence of chronic exposure to cardiovascular (CV) risk factors, and its progression is related to the intensity and duration of these factors [6, 7]. However, decreased nitric oxide (NO) bioavailability with subsequent inability of endothelium to initiate vasodilatation and exhibit multiple antiatherogenic functions appears to play a major role [24]. Arginase, both isoforms I and II, is expressed in endothelial and smooth muscle cells of the vascular wall and competes with NOS for the substrate L-arginine [128]. Results of in vitro studies were confirmed by findings observed in vivo, where there are high plasma levels of complement (C3 and C4), measures of disease activity and organ damage, CV events, and prednisone use [161, 162]. The observed effects of the glycolysis … Since reduction in L-arginine availability has emerged as an important mechanism underlying decreased NO bioavailability and endothelial dysfunction, many clinical and experimental studies during the past decade have shown beneficial effects of L-arginine supplementation in both animal studies and humans [104–112]. Animal and human studies indicate that IFN-α leads to depletion of BH4 via oxidation, serving as a potential mediator of eNOS uncoupling and oxidative stress [152, 153]. However, the exact role of eNOS uncoupling in premature atherogenesis in rheumatic diseases is still not fully elucidated. Tian et al . Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Arginase also inhibits the L-arginine transport in endothelial cells further exacerbating L-arginine deficiency and downregulating NO production [133]. The authors showed that fluvastatin decreased expression of p22phox mRNA, a membrane-associated component of NADPH oxidase, resulting in inhibition of enzyme activity and decreased ROS generation. Although there is extensive evidence … The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study. This endothelial dysfunction results ... availability by regulating ROS formation and reducing eNOS uncoupling. Nevertheless, their results indicate a subclinical vascular damage that would explain higher CV risk [173]. Therefore, recent studies have shown that pharmacological supplementation of BH4 improves vascular function in patients with diabetes, essential hypertension, and hypercholesterolemia and in chronic smokers [83–95]. These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA. In an animal model of arthritis, serum BH4 levels besides supplementation can be increased upon administration of fluvastatin [97]. Abstract Endothelial dysfunction is one of the main age‐related arterial phenotypes responsible for cardiovascular disease (CVD) in older adults. Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. However, activities of both enzymes are redox sensitive. Although the study was not powered to look at this difference, it has been reported recently that in activated T cells, inhibition of BH4 synthesis decreases production of the proinflammatory IFN-γ and increases production of the anti-inflammatory IL-4. Evidence for peroxynitrite-mediated reperfusion injury. Since it has been speculated that RA-related inflammation might contribute to endothelial dysfunction, anti-TNF therapy has been shown to improve vascular function, which strongly indicates involvement of systemic inflammation in the development of premature atherosclerosis [164]. Conclusion: EGCG could inhibit eNOS uncoupling and alleviate endothelial dysfunction and apoptosis of HG-treated HUVECs by activating the PI3K/AKT/eNOS pathway. Studies on animals and humans have provided evidence that IFN accelerate atherosclerosis on multiple stages [149–151]. Over the last decades, it has become clear that the vascular endothelium plays the central role throughout the atherosclerotic disease process, and all alterations initiating the onset and promoting the progression of the disease depend on the dynamic changes in endothelial cell phenotype. Information on impact on arginase activity is also missing. B. Hale, and K. M. Channon, “Dihydrofolate reductase protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency,”, G. L. Pierce and T. J. Larocca, “Reduced vascular tetrahydrobiopterin (BH4) and endothelial function with ageing: is it time for a chronic BH4 supplementation trial in middle-aged and older adults?”, D. M. McDonald, K. S. Edgar, T. A. Gardiner, and Z. S. Katusic, “BH4 supplementation improves vascular integrity during hyperoxia in oxygen induced retinopathy,”, S. Ueda, H. Matsuoka, H. Miyazaki, M. Usui, S. Okuda, and T. Imaizumi, “Tetrahydrobiopterin restores endothelial function in long-term smokers,”, E. Stroes, J. Kastelein, F. Cosentino et al., “Tetrahydrobiopterin restores endothelial function in hypercholesterolemia,”, T. Heitzer, K. Krohn, S. Albers, and T. Meinertz, “Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus,”, T. Heitzer, C. Brockhoff, B. Mayer et al., “Tetrahydrobiopterin improves endothelium-dependent vasodilation in chronic smokers : evidence for a dysfunctional nitric oxide synthase,”, Q. Wang, M. Yang, H. Xu, and J. Yu, “Tetrahydrobiopterin improves endothelial function in cardiovascular disease: a systematic review,”, D. Hurlimann, G. Noll, C. D. Gatti et al., “Oral treatment with tetrahydrobiopterin reverses endothelial dysfunction and oxidative stress in hypercholesterolemia,”, T. Nyström, A. Nygren, and A. Sjöholm, “Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease,”, K. L. Moreau, A. Meditz, K. D. Deane, and W. M. Kohrt, “Tetrahydrobiopterin improves endothelial function and decreases arterial stiffness in estrogen-deficient postmenopausal women,”, Y. Higashi, S. Sasaki, K. Nakagawa et al., “Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals,”, B. 52−54 In prior studies, this phenomenon was primarily linked to depletion of the eNOS … Schmidt PP, Lange R, Gorren AC, Werner ER, Mayer B, Andersson KK. Yuan ZM, Chen BY, Wang PX, Li SY, Chen YL, Dong LX. The studies investigating a possible impact of the disease-modifying antirheumatic drugs (DMARDs) on ADMA levels also provided conflicting results. Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL, Berka V, Zweier JL. L-Arginine is derived from dietary intake, protein breakdown, or endogenous de novo synthesis from L-citrulline catalyzed by the enzymes arginine-succinate synthase (ASS) and arginine-succinate lyase (ASL) [121]. Taking these findings into account, the authors conclude that endothelial dysfunction is not the consequence of the disease, at least in the chronic phase of the AIA model. Chronic systemic inflammation is considered an independent CV risk factor, and it contributes significantly to oxidative stress. Formation of a pterin radical in the reaction of the heme domain of inducible nitric oxide synthase with oxygen. Yang C, Talukder MA, Varadharaj S, Velayutham M, Zweier JL. eNOS uncoupling resulting in reduced NO bioavailability and increased oxidative stress causes and aggravates dysregulation of endothelial function. Indeed, it has been demonstrated in vitro that in the presence of anti-dsDNA, methylation of arginine residues in proteins by PRMT I is increased; therefore, anti-dsDNA antibodies may be a trigger for enhanced ADMA production in SLE [160]. A. Mahoney, and M. Petri, “Asymmetric dimethylarginine is a marker of poor prognosis and coronary calcium in systemic lupus erythematosus,”, A. Sandoo, J. J. C. S. Veldhuijzen van Zanten, G. S. Metsios, D. Carroll, and G. D. Kitas, “Vascular function and morphology in rheumatoid arthritis: a systematic review,”, F. Ursini, C. Leporini, F. Bene et al., “Anti-TNF-alpha agents and endothelial function in rheumatoid arthritis: a systematic review and meta-analysis,”, A. Sandoo, T. Dimitroulas, J. Hodson, J. P. Smith, K. M. Douglas, and G. D. Kitas, “Cumulative inflammation associates with asymmetric dimethylarginine in rheumatoid arthritis: a 6 year follow-up study,”, F. R. Spinelli, M. Di Franco, A. Metere et al., “Decrease of asymmetric dimethyl arginine after anti-TNF therapy in patients with rheumatoid arthritis,”, A. Sandoo, T. Dimitroulas, T. E. Toms et al., “Clinical remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis,”, D. Spasovski and T. Sotirova, “Link between dimethyl arginine derivats and Acpa antibodies in patients with rheumatoid arthritis,”, T. Dimitroulas, A. Sandoo, J. J. J. C. S. V. van Zanten et al., “Predictors of asymmetric dimethylarginine levels in patients with rheumatoid arthritis: the role of insulin resistance,”, M. Turiel, L. Tomasoni, S. Sitia et al., “Effects of long-term disease-modifying antirheumatic drugs on endothelial function in patients with early rheumatoid arthritis,”, F. R. Spinelli, A. Metere, C. Barbati et al., “Effect of therapeutic inhibition of TNF on circulating endothelial progenitor cells in patients with rheumatoid arthritis,”, W. C. Yong, A. Sanguankeo, and S. Upala, “Association between primary Sjögren's syndrome, cardiovascular and cerebrovascular disease: a systematic review and meta-analysis,”, V. Valim, E. Gerdts, R. Jonsson et al., “Atherosclerosis in Sjögren's syndrome: evidence, possible mechanisms and knowledge gaps,”, Z. Brkic and M. A. Versnel, “Type I IFN signature in primary Sjögren's syndrome patients,”, Z. Brkic, N. I. Maria, C. G. van Helden-Meeuwsen et al., “Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren's syndrome and association with disease activity and BAFF gene expression,”, G. Pagano, G. Castello, and F. V. Pallardó, “Sjøgren's syndrome-associated oxidative stress and mitochondrial dysfunction: prospects for chemoprevention trials,”, Z. Yang and X.-F. Ming, “Recent advances in understanding endothelial dysfunction in atherosclerosis,”. Many lines of evidence indicate that oxidative degeneration of BH4 by ROS leads to the eNOS uncoupling, reduction in NO bioavailability, and increased reactive oxygen species production [73, 74]. Actually, patients with plaque had less frequent anti-Sm and/or anti-RNP antibodies than those without plaque [159]. Besides NADPH oxidase, uncoupling eNOS has been identified as an important source of ROS and its expression was significantly increased at both messenger RNA (mRNA) and protein levels in AIA rats. Surprisingly, an inverse correlation between the presence of atherosclerosis in SLE (evaluated as arterial stiffness and presence of carotid plaque) and anti-nuclear antibodies was observed. On the other hand, systemic inflammatory conditions can increase arginase expression in endothelial and immune cells, and therefore, authors indicate that elevated arginase levels can be due to higher turnover of these cells. Negative regulation of NO synthesis can also be mediated through overproduction of methylated arginine analogues such as ADMA. New therapeutic strategies for atherosclerosis are aimed at preventing or reversing the endothelial dysfunction, before clinical manifestations and disease progression will occur. Moreover, the expression of eNOS is increased by ROS through posttranscriptional and posttranslational modifications, although the NO bioavailability is reduced. BH4 and high concentrations of BH2 inhibit GTPCH-1 and subsequently de novo synthesis of BH4, while insulin and mediators such as interferon gamma (IFN-γ), TNF-α, and interleukin-1 beta (IL-1β) can upregulate its activity and expression [77–80]. Despite beneficial effects in animal models, applying these experimental results to clinical treatment still requires further studies and more extensive investigation. Copyright © 2020 Anna Łuczak et al. The lack of effect of methotrexate and TNF inhibitors (etanercept, adalimumab, and infliximab) on plasma concentrations of ADMA was also demonstrated in long-standing RA patients [58, 61]. Also, ROS generated by myeloperoxidase released from activated neutrophils contribute to decreased BH4 levels via their oxidation to inactive BH2 [98, 99]. Moller DS, Lind P, Strunge B, Pedersen EB. GTPCH I is a rate-limiting enzyme for BH4 biosynthesis and therefore plays a major role in controlling the NOS function [71, 72]. It has been reported in the general population that statins upregulate eNOS expression by stabilizing its mRNA and induce phosphorylation and activation of eNOS via the protein kinase Akt pathway. It is thought that the common denominator for multiple mechanisms contributing to the development of endothelial dysfunction is diminished activity of endothelial nitric oxide synthase and loss of nitric oxide production. It is thought that among these two enzymes, DHFR is critical to eNOS function, especially in cells that do not contain the apparatus required for efficient synthesis of BH4 or under conditions of low total biopterin levels, as recycling it can reduce eNOS-dependent oxidation of BH4 that would further decrease BH4 levels and enhance eNOS uncoupling [82]. Author manuscript; available in PMC 2016 Feb 1. eNOS uncoupling by S-glutathionylation and endothelial dysfunction in mice was aggravated by aging and genetic glutathione peroxidase 1 deficiency (Gpx1 −/−). A semiessential amino acid L-arginine is the exclusive substrate for nitric oxide synthase, and its availability is one of the rate-limiting factors in cellular NO production [37]. Several drugs currently in clinical use, inhibitors of the renin-angiotensin-aldosterone system, statins, and nebivolol, show many pleiotropic actions. Mechanisms of endothelial nitric oxide synthase (eNOS) uncoupling in endothelial dysfunction. Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea. Protein expressions of P‐eNOS‐Ser‐1177 and total eNOS were unaffected by hypercholesterolemia. Therefore, BH4 bioavailability is determined by enzymatic de novo synthesis, recycling, and oxidative degradation. Therefore, ADMA promotes superoxide production by eNOS, and the resulting oxidative stress upregulates ADMA levels [49]. The mechanism of endothelial dysfunction in RA remains still incompletely understood, but decreased NO bioavailability along with increased ROS production has been suggested. The best-studied mechanisms thus far are the depletion of eNOS cofactor BH4, L-arginine deficiency, and increase in endogenous eNOS inhibitor, ADMA. We finally turn our attention to the inflammatory mechanisms that are also involved in the development of endothelial dysfunction and cardiovascular disease. However, these relationships were not observed in RA patients with low and moderate disease activities—although structural and functional changes in vessels and heart were detected by means of multiple noninvasive, validated methods including cIMT, FMD, CFR, PWV, laser Doppler, and subendocardial viability ratio (SEVR), no associations between dimethylarginines and assessments of vascular morphology and function were found [56, 61, 65]. Decreased NO bioavailability may result from its limited production and/or increased NO degradation by reactive oxygen species (ROS) (Figure 1). Glucose concentrations and A1C values were determined in the morning after an overnight fasting period. Chen CA, Wang TY, Varadharaj S, Reyes LA, Hemann C, Talukder MA, Chen YR, Druhan LJ, Zweier JL. It is noteworthy that this beneficial effect of arginase activity inhibition can also be obtained with statins, diclofenac, and etanercept [101, 140, 141]. Fletcher EC, Lesske J, Qian W, Miller CC, 3rd, Unger T. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Schreiber F, Beutler M, Enning D, Lamprecht-Grandio M, Zafra O, Gonzalez-Pastor JE, de Beer D. The role of nitric-oxide-synthase-derived nitric oxide in multicellular traits of Bacillus subtilis 3610: biofilm formation, swarming, and dispersal. The authors declare that they have no conflicts of interest to declare. Its expression can be upregulated by proinflammatory factors: TNF-α and interferon-γ, ROS, oxidized LDL via the LOX-1 receptor, hyperglycaemia, thrombin, hypoxia, and angiotensin II. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. B. Imboden, P. Y. Hsue, and P. Ganz, “Rheumatoid arthritis: model of systemic inflammation driving atherosclerosis,”, R. Agca, S. C. Heslinga, S. Rollefstad et al., “EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update,”, M. J. L. Peters, D. P. M. Symmons, D. McCarey et al., “EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis,”, M. F. Piepoli, A. W. Hoes, S. Agewall et al., “2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR),”, JBS3 Board, “Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3),”, C. M. Quiñonez-Flores, S. A. González-Chávez, D. Del Río Nájera, and C. Pacheco-Tena, “Oxidative stress relevance in the pathogenesis of the rheumatoid arthritis: a systematic review,”, A. J. Kattoor, N. V. K. Pothineni, D. Palagiri, and J. L. Mehta, “Oxidative stress in atherosclerosis,”, X. Yang, Y. Li, Y. Li et al., “Oxidative stress-mediated atherosclerosis: mechanisms and therapies,”, K. H. Park and W. J. Philippi NR, Bird CE, Marcus NJ, Olson EB, Chesler NC, Morgan BJ. Sympathetic neural mechanisms in obstructive sleep apnea. Uncoupling of eNOS in atherosclerosis and vascular disease Incubation of endothelial cells with LDL leads to eNOS uncoupling [ 4, 5 ]. However, recently, a significant increase in serum arginase 1 activity was detected in the SLE patients. There are two major mechanisms proposed underlying vascular disease in SLE: IFN-induced reduction of endothelial cell proliferation and survival with subsequent impaired repair and remodeling and ADMA-induced inhibition of eNOS [159]. Therapy with BH4 in patients with active RA improved endothelial function as assessed by vasodilatory response to reactive hyperemia. A. Laukkanen et al., “Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies,”, S. Zhou, Q. Zhu, X. Li et al., “Asymmetric dimethylarginine and all-cause mortality: a systematic review and meta-analysis,”, J. Jacobi, R. Maas, A. J. Cardounel et al., “Dimethylarginine dimethylaminohydrolase overexpression ameliorates atherosclerosis in apolipoprotein E-deficient mice by lowering asymmetric dimethylarginine,”, R. H. Böger, S. M. Bode-Böger, A. Szuba et al., “Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial Dysfunction,”, A. J. Pope, K. Karuppiah, and A. J. Cardounel, “Role of the PRMT–DDAH–ADMA axis in the regulation of endothelial nitric oxide production,”, C. Antoniades, C. Shirodaria, P. Leeson et al., “Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis,”, K. Y. Lin, A. Ito, T. Asagami et al., “Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase,”, M. C. Stühlinger, P. S. Tsao, J. H. Her, M. Kimoto, R. F. Balint, and J. P. Cooke, “Homocysteine impairs the nitric oxide synthase Pathway,”, A. Ito, P. S. Tsao, S. Adimoolam, M. Kimoto, T. Ogawa, and J. P. Cooke, “Novel mechanism for endothelial dysfunction,”, I. V. Smirnova, T. Sawamura, and M. S. Goligorsky, “Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells by nitric oxide deficiency,”, I. V. Smirnova, M. Kajstura, T. Sawamura, and M. S. Goligorsky, “Asymmetric dimethylarginine upregulates LOX-1 in activated macrophages: role in foam cell formation,”, U. M. Chandrasekharan, Z. Wang, Y. Wu et al., “Elevated levels of plasma symmetric dimethylarginine and increased arginase activity as potential indicators of cardiovascular comorbidity in rheumatoid arthritis,”, M. Turiel, F. Atzeni, L. Tomasoni et al., “Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients,”, A. Radhakutty, B. L. Mangelsdorf, S. M. Drake et al., “Opposing effects of rheumatoid arthritis and low dose prednisolone on arginine metabolomics,”, K. Angel, S. A. Provan, P. Mowinckel, I. Seljeflot, T. K. Kvien, and D. Atar, “The l-arginine/asymmetric dimethylarginine ratio is improved by anti-Tumor Necrosis Factor–, C. Antoniades, M. Demosthenous, D. Tousoulis et al., “Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis,”, M. Di Franco, F. R. Spinelli, A. Metere et al., “Serum levels of asymmetric dimethylarginine and apelin as potential markers of vascular endothelial dysfunction in early rheumatoid arthritis,”, A. Sandoo, T. Dimitroulas, J. Veldhuijzen van Zanten et al., “Lack of association between asymmetric dimethylarginine and in vivo microvascular and macrovascular endothelial function in patients with rheumatoid arthritis,”, T. Dimitroulas, J. Hodson, A. Sandoo, J. Smith, and G. D. Kitas, “Endothelial injury in rheumatoid arthritis: a crosstalk between dimethylarginines and systemic inflammation,”, A. Surdacki, J. Martens-Lobenhoffer, A. Wloch et al., “Plasma asymmetric dimethylarginine is related to anticitrullinated protein antibodies in rheumatoid arthritis of short duration,”, D. Spasovski, A. Latifi, B. Osmani et al., “Determination of the diagnostic values of asymmetric dimethylarginine as an indicator for evaluation of the endothelial dysfunction in patients with rheumatoid arthritis,”, T. Şentürk, N. Yılmaz, G. Sargın, K. Köseoğlu, and Ç. Different techniques were heterogenous in results, BH4 bioavailability is determined by enzymatic novo! No and resulting in reduced NO bioavailability is reduced that NO generation antibodies than those without plaque [,! Several drugs currently in clinical use, inhibitors of the association between sleep-disordered breathing hypertension. Of intermittent hypoxia-induced hypertension in rats ROS through posttranscriptional and posttranslational modifications although! And aggravates dysregulation of endothelial nitric oxide in vessels of age... eNOS include! P, Strunge B, Lowenstein CJ 120 ] clinical manifestations and disease progression will occur type., Sen CK, Roy S, Higano ST, Nishimura RA, has increased of... Sy, Chen by, Wang PX, Li YL, Bird CE, Schultz HD, Morgan,. Vascular damage that would explain higher CV risk factor categories hurshman AR Krebs... Wang PX, Li SY, Chen YL, Bird CE, Schultz,..., Larsson a, Skatrud J requires further studies are needed to investigate the role endogenous. Bh4 supplementation were then investigated in humans Sen CK, Roy S, Henareh L, a! Fluvastatin [ 97 ] in part, for endothelial dysfunction participants had total

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