Increased plasma tetrahydrobiopterin in septic shock is a possible therapeutic target

Hoshiai, Kiyotaka; Hattan, Naoichiro; Fukuyama, Naoto; Tadaki, Futoshi; Hida, Miho; Saitō, Akira; Nakanishi, Nobuo; Hattori, Yoshiyuki; Nakazawa, Hiroe

doi:10.1016/s0928-4680(00)00063-8

Cited by 13 publications

(13 citation statements)

References 30 publications

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“…BH 4 in human plasma typically comprises around 50% to 80% of total biopterins whereas in guinea pigs, more than 90% is on the reduced form. Compared to other animal species, guinea pig biopterin plasma levels are comparable to those found in studies using mice and rats [57,66,83,[85][86][87][88][89][90][91], whereas larger animals such as dogs, cats, and monkeys have biopterin levels more similar to those found in humans [65,66,83,92]. Thus, one limitation of our study is that the impact of vitamin C deficiency on biopterin status may not translate between guinea pigs and humans as only the vitamin C level is similar between the two species while guinea pig biopterin levels are higher.…”

Section: Discussionsupporting

confidence: 63%

Guinea pig ascorbate status predicts tetrahydrobiopterin plasma concentration and oxidation ratio in vivo

et al. 2013

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Section: Discussionsupporting

confidence: 63%

Guinea pig ascorbate status predicts tetrahydrobiopterin plasma concentration and oxidation ratio in vivo

et al. 2013

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“…Septic patients have been shown to have significant elevations in plasma biopterins as well as nitrites and nitrates (115). A similar pattern is seen in LPS-treated rats, and is reduced when following plasma endotoxin adsorption onto polymyxin B fibers (115).…”

Section: Fig 8 the Gch Transgenic Mousementioning

confidence: 81%

“…In a model of Staphylococcus aureus postburn sepsis, rat GCH1 mRNA was induced in multiple tissues and significantly correlated with multiple organ dysfunction (240). Septic patients have been shown to have significant elevations in plasma biopterins as well as nitrites and nitrates (115). A similar pattern is seen in LPS-treated rats, and is reduced when following plasma endotoxin adsorption onto polymyxin B fibers (115).…”

Section: Fig 8 the Gch Transgenic Mousementioning

confidence: 89%

Tetrahydrobiopterin in Cardiovascular Health and Disease

Bendall

Douglas

McNeill

et al. 2014

Antioxidants & Redox Signaling

194

187

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Tetrahydrobiopterin (BH4) functions as a cofactor for several important enzyme systems, and considerable evidence implicates BH4 as a key regulator of endothelial nitric oxide synthase (eNOS) in the setting of cardiovascular health and disease. BH4 bioavailability is determined by a balance of enzymatic de novo synthesis and recycling, versus degradation in the setting of oxidative stress. Augmenting vascular BH4 levels by pharmacological supplementation has been shown in experimental studies to enhance NO bioavailability. However, it has become more apparent that the role of BH4 in other enzymatic pathways, including other NOS isoforms and the aromatic amino acid hydroxylases, may have a bearing on important aspects of vascular homeostasis, inflammation, and cardiac function. This article reviews the role of BH4 in cardiovascular development and homeostasis, as well as in pathophysiological processes such as endothelial and vascular dysfunction, atherosclerosis, inflammation, and cardiac hypertrophy. We discuss the therapeutic potential of BH4 in cardiovascular disease states and attempt to address how this modulator of intracellular NO-redox balance may ultimately provide a powerful new treatment for many cardiovascular diseases. Antioxid. Redox Signal. 20, 3040-3077.

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“…Septic shock is an overwhelming inflammatory response to a microbial infection encompassing unregulated NO production in the vasculature, leading to profound hypotension which can ultimately lead to reduced organ perfusion and tissue death (Cobb et al, 1996) (Hoshiai et al, 2001). In patients with septic shock, it has been observed that there is a significant rise in total serum biopterin concentrations (biopterin is a measurable correlate of BH4 in the plasma) (Hoshiai et al, 2001). Therefore, limiting BH4 bioavailability and hence excessive NO production, may present a means to regulate vascular function in septic shock (Cobb et al, 1996) (Hoshiai et al, 2001).…”

Section: Disorders Of No Metabolism: the Potential Role Of Bh4 In Sepmentioning

confidence: 99%

“…In patients with septic shock, it has been observed that there is a significant rise in total serum biopterin concentrations (biopterin is a measurable correlate of BH4 in the plasma) (Hoshiai et al, 2001). Therefore, limiting BH4 bioavailability and hence excessive NO production, may present a means to regulate vascular function in septic shock (Cobb et al, 1996) (Hoshiai et al, 2001). Inhibiting BH4 biosynthesis has been shown to elicit protective effects in animal models of septic shock (Li, et al, 2002).…”

Section: Disorders Of No Metabolism: the Potential Role Of Bh4 In Sepmentioning

confidence: 99%

Investigating the interaction between GTP-cyclohydrolase1 and its feedback regulatory protein

et al. 2012

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GTP-cyclohydrolase-1 (GTPCH1) catalyses the rate-limiting step in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for enzymes including aromatic amino acid hydroxylases and nitric oxide synthases. Strategies that increase vascular BH4 biosynthesis represent a promising therapeutic approach for the treatment of endothelial dysfunction. GTPCH1 is subject to feedback and feed-forward regulation by BH4 and L-phenylalanine (L-phe) respectively, via an allosteric protein interaction with GTPCH1 feedback regulatory protein (GFRP). The aim of this thesis was to investigate the GTPCH1-GFRP interaction using recombinant proteins, and to validate the functional significance of the interaction in the vasculature using animal models. Human GTPCH1 and GFRP proteins were recombinantly expressed. Studies compared the activity and protein interactions of native GTPCH1 with a truncated mutant. A kinetic GTPCH1 activity assay was modified to enable a high-throughput screen of a fragment library. GTPCH1-GFRP interactions were assessed using surface plasmon resonance (SPR). Finally, in-vivo and ex-vivo functional studies in rodents investigated the effects of L-phe on vascular function and BH4 levels. Studies using recombinant proteins revealed the activity of truncated GTPCH1 exceeds that of native GTPCH1. A high-throughput screen successfully identified four compounds that modulate GTPCH1 activity. Biophysical analysis (SPR) demonstrated that both native and truncated GTPCH1 bind to GFRP in the absence of natural ligands. The kinetics and binding rate constants have been reported for the first time. In functional studies, oral L-phe supplementation in rodents led to a rise of BH4 levels within aortic tissue, and reversed vascular dysfunction observed in vessels obtained from spontaneously hypertensive rats. This thesis demonstrates that modulation of the GTPCH1-GFRP interactions represents a novel therapeutic target to regulate endogenous BH4 levels. SPR data suggests that GTPCH1 and 2 GFRP are constitutively bound in-vivo and indicate that the N-terminal region of GTPCH1 may directly interact with GFRP and modulate basal enzyme activity. The functional effects of L-phe on vascular BH4 levels and function, validate the potential of the GTPCH1-GFRP pathway as a therapeutic target for cardiovascular disease. 3

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Increased plasma tetrahydrobiopterin in septic shock is a possible therapeutic target

Cited by 13 publications

References 30 publications

Guinea pig ascorbate status predicts tetrahydrobiopterin plasma concentration and oxidation ratio in vivo

Guinea pig ascorbate status predicts tetrahydrobiopterin plasma concentration and oxidation ratio in vivo

Tetrahydrobiopterin in Cardiovascular Health and Disease

Investigating the interaction between GTP-cyclohydrolase1 and its feedback regulatory protein

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