Kinetics of acid-induced degradation of tetra- and dihydrobiopterin in relation to their relevance as biomarkers of endothelial function

Mortensen, Alan; Lykkesfeldt, Jens

doi:10.3109/1354750x.2012.730552

Cited by 11 publications

(9 citation statements)

References 31 publications

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“…Furthermore, tetrahydrobiopterin (BH 4 ) providing reducing equivalents for eNOS 54 as well as its oxidation products dihydrobiopterin (BH 2 ) and biopterin were measured in plasma as indicators for vascular oxidative stress using HPLC with fluorescence detection employing iodine oxidation as described by Fukushima and Nixon 55 . To prevent ex vivo oxidation when measuring biopterins, 1 ml of whole blood was drawn with a K 3 -EDTA flushed syringe and immediately added to a microcentrifuge tube containing 25 µl of 2.5% (w/v) dithioerythriol (DTE) in Milli-Q (18.2 MΩ) water 56 . The sample was then centrifuged (4 °C; 15000 × g; 1 minute) to obtain plasma, which was immediately stored at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

Rune

Rolin

Lykkesfeldt

et al. 2018

Sci Rep

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In the apolipoprotein E–deficient mouse, the gut microbiota has an impact on the development of atherosclerosis, but whether such correlations are also present in rats requires investigation. Therefore, we studied female SD-Apoetm1sage (Apoe−/−) rats fed either a Western diet or a low-fat control diet with or without gluten, which is known to promote gut microbiota changes, until 20 weeks of age. We hypothesized that the manifestation of atherosclerosis would be more severe in Apoe−/− rats fed the Western high-fat diet, as compared with rats fed the low-fat diet, and that atherosclerosis would be accelerated by gluten. Both Western diet-feeding and gluten resulted in significant changes in gut microbiota, but the microbiota impact of gluten was transient. Compared with Apoe−/− rats fed a low-fat diet, Western diet-fed Apoe−/− rats were heavier and became glucose intolerant with increased levels of oxidative stress. They developed early fatty streak lesions in their aortic sinus, while there was no evidence of atherosclerosis in the thoracic aorta. No conclusions could be made on the impact of gluten on atherosclerosis. Although Western diet-fed Apoe−/− rats exhibited a more human-like LDL dominated blood lipid profile, signs of obesity, type 2 diabetes and cardiovascular disease were modest.

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Section: Methodsmentioning

confidence: 99%

Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

Rune

Rolin

Lykkesfeldt

et al. 2018

Sci Rep

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“…Analysis included a complete blood count (CBC) and serum biochemistry profile. For biopterin analysis, blood was collected in K 3 EDTA tubes (4 mL) with 100 μL freshly made 1,4‐Dithioerythritol (DTE) solution (40 mg DTE in 1,000 μL Milli‐Q [18.2 MΩ] water) added to minimize oxidation during analysis . Samples were mixed gently before centrifugation (3,000 × g , 3 minutes, at 4°C) and plasma was frozen immediately at −80°C until analysis.…”

Section: Methodsmentioning

confidence: 99%

Biopterin Status in Dogs with Myxomatous Mitral Valve Disease is Associated with Disease Severity and Cardiovascular Risk Factors

Reimann

Häggström

Mortensen

et al. 2014

Veterinary Internal Medicne

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BackgroundEndothelial dysfunction (ED) has been suggested to be associated with myxomatous mitral valve disease (MMVD) in dogs. Tetrahydrobiopterin (BH4) is an important cofactor for production of the endothelium‐derived vasodilator nitric oxide (NO). Under conditions of oxidative stress, BH4 is oxidized to the biologically inactive form dihydrobiopterin (BH2). Thus, plasma concentrations of BH2 and BH4 may reflect ED and oxidative stress.ObjectiveTo determine plasma concentrations of BH2 and BH4 in dogs with different degrees of MMVD.AnimalsEighty‐four privately owned dogs grouped according to ACVIM guidelines (37 healthy control dogs including 13 Beagles and 24 Cavalier King Charles Spaniels [CKCSs], 33 CKCSs with MMVD of differing severity including 18 CKCSs [group B1] and 15 CKCSs [group B2], and 14 dogs of different breeds with clinical signs of congestive heart failure [CHF] because of MMVD [group C]).MethodsDogs underwent clinical examination including echocardiography. Plasma concentrations of BH2 and BH4 were measured using high‐performance liquid chromatography with fluorescence detection.ResultsHigher plasma BH4 and BH2 concentrations were found with dogs in CHF compared with all other groups (control, B1 and B2; P ≤ .001). Females had higher concentrations of BH4 and BH4/BH2 (P ≤ .0003). BH4/BH2 was found to decrease with age (P < .0001). Cardiovascular risk factors in humans such as passive smoking (P ≤ .01) and increased body weight (P ≤ .009) were associated with lower BH4 concentrations.Conclusions and Clinical ImportanceAge, sex, body weight, passive smoking, and cardiac status are associated with plasma biopterin concentration in dogs. Additional studies should clarify the clinical implications of the findings.

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“…Thus, 41 nM BH 4 was completely converted to BH 2 in 15 min at 4°C in 0.1 M HCl, whereas BH 4 in a 415 nM solution under the same conditions was only 1% degraded and at higher concentrations of BH 4 an even smaller percentage was oxidized [16]. Secondly, the stability of BH 4 in aqueous solution is dependent on pH showing increased stability at low pH [3]. In Table 1 is summarized the observed effects of Asc on the stability of BH 4 in vitro.…”

Section: In Vitro Studiesmentioning

confidence: 94%

“…The most reduced form, BH 4 , is easily oxidized to a quinoid form of BH 2 , qBH 2 , which rapidly rearranges to BH 2 ; BH 2 may then be further oxidized to biopterin. However, in contrast to BH 4 , BH 2 is relatively stable and is only slowly oxidized [3]. BH 4 and BH 2 have been shown to bind to eNOS with similar affinity (K d % 80 nM) [4].…”

Section: Introductionmentioning

confidence: 99%

Does vitamin C enhance nitric oxide bioavailability in a tetrahydrobiopterin-dependent manner? In vitro, in vivo and clinical studies

Mortensen

Lykkesfeldt

2014

Nitric Oxide

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Ascorbate (Asc) has been shown to increase nitric oxide (NO) bioavailability and thereby improve endothelial function in patients showing signs of endothelial dysfunction. Tetrahydrobiopterin (BH₄) is a co-factor of endothelial nitric oxide synthase (eNOS) which may easily become oxidized to the inactive form dihydrobiopterin (BH₂). Asc may increase NO bioavailability by a number of mechanisms involving BH₄ and eNOS. Asc increases BH₄ bioavailability by either reducing oxidized BH₄ or preventing BH₄ from becoming oxidized in the first place. Asc could also increase NO bioavailability in a BH₄-independent manner by increasing eNOS activity by changing its phosphorylation and S-nitrosylation status or by upregulating eNOS expression. In this review, we discuss the putative mechanisms by which Asc may increase NO bioavailability through its interactions with BH₄ and eNOS.

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Kinetics of acid-induced degradation of tetra- and dihydrobiopterin in relation to their relevance as biomarkers of endothelial function

Cited by 11 publications

References 31 publications

Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

Biopterin Status in Dogs with Myxomatous Mitral Valve Disease is Associated with Disease Severity and Cardiovascular Risk Factors

Does vitamin C enhance nitric oxide bioavailability in a tetrahydrobiopterin-dependent manner? In vitro, in vivo and clinical studies

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