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Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches.

Hussein D, Starr A, Heikal L, McNeill E, Channon KM, Brown PR, Sutton BJ, McDonnell JM, Nandi M - Br. J. Pharmacol. (2015)

Bottom Line: Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential.We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo.In vivo, L-phe challenge induced a sustained elevation of aortic BH4 , an effect absent in GCH1(fl/fl)-Tie2Cre mice.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK.

No MeSH data available.


Related in: MedlinePlus

Effects of L-phenylalanine (L-phe) challenge on superoxide anion, nitrite and 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) levels in cultured endothelial (sEnd1) cells in the presence and absence of human modified oxidized lipoprotein. (A) Cellular superoxide anion concentration as quantified by mean arbitrary lights units (lucigenin chemiluminescence) using superoxide dismutase as positive control, (B) nitrite accumulation in media, (C) cellular BH4 concentration, in sEnd 1 cells untreated (UT) or treated with Human modified oxidized lipoprotein (100 μM, 2 h) in the absence or presence of L-phe (500 μM, 0.5 h); n = 4–9, mean ± SEM. *P < 0.05, significantly different from untreated control).
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fig03: Effects of L-phenylalanine (L-phe) challenge on superoxide anion, nitrite and 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) levels in cultured endothelial (sEnd1) cells in the presence and absence of human modified oxidized lipoprotein. (A) Cellular superoxide anion concentration as quantified by mean arbitrary lights units (lucigenin chemiluminescence) using superoxide dismutase as positive control, (B) nitrite accumulation in media, (C) cellular BH4 concentration, in sEnd 1 cells untreated (UT) or treated with Human modified oxidized lipoprotein (100 μM, 2 h) in the absence or presence of L-phe (500 μM, 0.5 h); n = 4–9, mean ± SEM. *P < 0.05, significantly different from untreated control).

Mentions: Addition of human modified oxidized lipoprotein to endothelial cells led to a significant elevation of superoxide anion (Figure 3A), reduction in nitrite (Figure 3B) and reduction in BH4 (Figure 3C) compared to baseline and consistent with published observations (Bowers et al., 2011). Application of L-phe (500 μM, 30 min) restored superoxide, nitrite and BH4 towards baseline levels (Figure 3A–C).


Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches.

Hussein D, Starr A, Heikal L, McNeill E, Channon KM, Brown PR, Sutton BJ, McDonnell JM, Nandi M - Br. J. Pharmacol. (2015)

Effects of L-phenylalanine (L-phe) challenge on superoxide anion, nitrite and 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) levels in cultured endothelial (sEnd1) cells in the presence and absence of human modified oxidized lipoprotein. (A) Cellular superoxide anion concentration as quantified by mean arbitrary lights units (lucigenin chemiluminescence) using superoxide dismutase as positive control, (B) nitrite accumulation in media, (C) cellular BH4 concentration, in sEnd 1 cells untreated (UT) or treated with Human modified oxidized lipoprotein (100 μM, 2 h) in the absence or presence of L-phe (500 μM, 0.5 h); n = 4–9, mean ± SEM. *P < 0.05, significantly different from untreated control).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543619&req=5

fig03: Effects of L-phenylalanine (L-phe) challenge on superoxide anion, nitrite and 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) levels in cultured endothelial (sEnd1) cells in the presence and absence of human modified oxidized lipoprotein. (A) Cellular superoxide anion concentration as quantified by mean arbitrary lights units (lucigenin chemiluminescence) using superoxide dismutase as positive control, (B) nitrite accumulation in media, (C) cellular BH4 concentration, in sEnd 1 cells untreated (UT) or treated with Human modified oxidized lipoprotein (100 μM, 2 h) in the absence or presence of L-phe (500 μM, 0.5 h); n = 4–9, mean ± SEM. *P < 0.05, significantly different from untreated control).
Mentions: Addition of human modified oxidized lipoprotein to endothelial cells led to a significant elevation of superoxide anion (Figure 3A), reduction in nitrite (Figure 3B) and reduction in BH4 (Figure 3C) compared to baseline and consistent with published observations (Bowers et al., 2011). Application of L-phe (500 μM, 30 min) restored superoxide, nitrite and BH4 towards baseline levels (Figure 3A–C).

Bottom Line: Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential.We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo.In vivo, L-phe challenge induced a sustained elevation of aortic BH4 , an effect absent in GCH1(fl/fl)-Tie2Cre mice.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK.

No MeSH data available.


Related in: MedlinePlus