2,4-Diamino-6-hydroxypyrimidine (DAHP) suppresses cytokine-induced VCAM-1 expression on the cell surface of human umbilical vein endothelial cells in a BH 4 -independent manner

Kazuhisa Ikemoto, Takashi Matsumoto, Masatsugu Ohtsuki, Mitsuyasu Itoh, Shin Tada, Yasuhiro Udagawa, Chiho Ichinose, Kazunao Kondo, Takahide Nomura

Research output: Contribution to journalArticle

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Abstract

2,4-Diamino-6-hydroxypyrimidine (DAHP) is considered a specific inhibitor of BH 4 biosynthesis and is widely used in order to elucidate the possible biological function of BH 4 in various cells. In the present study, we found that both the synthesis of tetrahydrobiopterin (BH 4 ) and expression of vascular cell adhesion molecule 1 (VCAM-1) were increased in human umbilical vein endothelial cells (HUVEC) treated with proinflammatory cytokines. Thus we examined the effects of DAHP to clarify whether BH 4 might be involved in the expression of VCAM-1 in HUVEC. DAHP reduced the levels of both BH 4 and VCAM-1 induced by TNF-α and IFN-γ. However, the dose-response curves of DAHP for the suppression of the VCAM-1 level and that of BH 4 level were markedly different. Supplementation with sepiapterin failed to restore the depressed VCAM-1 level, although it completely restored the BH 4 level. Furthermore, DAHP significantly reduced the VCAM-1 level under the experimental conditions using TNF-α alone, which failed to induce BH 4 production. Taken together, these results indicate that DAHP inhibited the expression of VCAM-1 in a BH 4 -independent manner in HUVEC. In the present study, we also found that DAHP significantly suppressed the accumulation of cytokine-induced NF-κB (p65) in the nucleus as well as the mRNA levels of VCAM-1 and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH 4 synthesis. The data obtained in this study suggest that DAHP reduced VCAM-1 and GTPCH protein synthesis at least partially via suppressing the NF-κB level in the nucleus of HUVEC.

Original languageEnglish
Pages (from-to)960-965
Number of pages6
JournalBiochimica et Biophysica Acta - General Subjects
Volume1780
Issue number7-8
DOIs
Publication statusPublished - 01-07-2008

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Vascular Cell Adhesion Molecule-1
Endothelial cells
Human Umbilical Vein Endothelial Cells
Cytokines
GTP Cyclohydrolase
2,4-diaminohypoxanthine
Biosynthesis
Messenger RNA
Enzymes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Ikemoto, Kazuhisa ; Matsumoto, Takashi ; Ohtsuki, Masatsugu ; Itoh, Mitsuyasu ; Tada, Shin ; Udagawa, Yasuhiro ; Ichinose, Chiho ; Kondo, Kazunao ; Nomura, Takahide. / 2,4-Diamino-6-hydroxypyrimidine (DAHP) suppresses cytokine-induced VCAM-1 expression on the cell surface of human umbilical vein endothelial cells in a BH 4 -independent manner In: Biochimica et Biophysica Acta - General Subjects. 2008 ; Vol. 1780, No. 7-8. pp. 960-965.
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abstract = "2,4-Diamino-6-hydroxypyrimidine (DAHP) is considered a specific inhibitor of BH 4 biosynthesis and is widely used in order to elucidate the possible biological function of BH 4 in various cells. In the present study, we found that both the synthesis of tetrahydrobiopterin (BH 4 ) and expression of vascular cell adhesion molecule 1 (VCAM-1) were increased in human umbilical vein endothelial cells (HUVEC) treated with proinflammatory cytokines. Thus we examined the effects of DAHP to clarify whether BH 4 might be involved in the expression of VCAM-1 in HUVEC. DAHP reduced the levels of both BH 4 and VCAM-1 induced by TNF-α and IFN-γ. However, the dose-response curves of DAHP for the suppression of the VCAM-1 level and that of BH 4 level were markedly different. Supplementation with sepiapterin failed to restore the depressed VCAM-1 level, although it completely restored the BH 4 level. Furthermore, DAHP significantly reduced the VCAM-1 level under the experimental conditions using TNF-α alone, which failed to induce BH 4 production. Taken together, these results indicate that DAHP inhibited the expression of VCAM-1 in a BH 4 -independent manner in HUVEC. In the present study, we also found that DAHP significantly suppressed the accumulation of cytokine-induced NF-κB (p65) in the nucleus as well as the mRNA levels of VCAM-1 and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH 4 synthesis. The data obtained in this study suggest that DAHP reduced VCAM-1 and GTPCH protein synthesis at least partially via suppressing the NF-κB level in the nucleus of HUVEC.",
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2,4-Diamino-6-hydroxypyrimidine (DAHP) suppresses cytokine-induced VCAM-1 expression on the cell surface of human umbilical vein endothelial cells in a BH 4 -independent manner . / Ikemoto, Kazuhisa; Matsumoto, Takashi; Ohtsuki, Masatsugu; Itoh, Mitsuyasu; Tada, Shin; Udagawa, Yasuhiro; Ichinose, Chiho; Kondo, Kazunao; Nomura, Takahide.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1780, No. 7-8, 01.07.2008, p. 960-965.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 2,4-Diamino-6-hydroxypyrimidine (DAHP) suppresses cytokine-induced VCAM-1 expression on the cell surface of human umbilical vein endothelial cells in a BH 4 -independent manner

AU - Ikemoto, Kazuhisa

AU - Matsumoto, Takashi

AU - Ohtsuki, Masatsugu

AU - Itoh, Mitsuyasu

AU - Tada, Shin

AU - Udagawa, Yasuhiro

AU - Ichinose, Chiho

AU - Kondo, Kazunao

AU - Nomura, Takahide

PY - 2008/7/1

Y1 - 2008/7/1

N2 - 2,4-Diamino-6-hydroxypyrimidine (DAHP) is considered a specific inhibitor of BH 4 biosynthesis and is widely used in order to elucidate the possible biological function of BH 4 in various cells. In the present study, we found that both the synthesis of tetrahydrobiopterin (BH 4 ) and expression of vascular cell adhesion molecule 1 (VCAM-1) were increased in human umbilical vein endothelial cells (HUVEC) treated with proinflammatory cytokines. Thus we examined the effects of DAHP to clarify whether BH 4 might be involved in the expression of VCAM-1 in HUVEC. DAHP reduced the levels of both BH 4 and VCAM-1 induced by TNF-α and IFN-γ. However, the dose-response curves of DAHP for the suppression of the VCAM-1 level and that of BH 4 level were markedly different. Supplementation with sepiapterin failed to restore the depressed VCAM-1 level, although it completely restored the BH 4 level. Furthermore, DAHP significantly reduced the VCAM-1 level under the experimental conditions using TNF-α alone, which failed to induce BH 4 production. Taken together, these results indicate that DAHP inhibited the expression of VCAM-1 in a BH 4 -independent manner in HUVEC. In the present study, we also found that DAHP significantly suppressed the accumulation of cytokine-induced NF-κB (p65) in the nucleus as well as the mRNA levels of VCAM-1 and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH 4 synthesis. The data obtained in this study suggest that DAHP reduced VCAM-1 and GTPCH protein synthesis at least partially via suppressing the NF-κB level in the nucleus of HUVEC.

AB - 2,4-Diamino-6-hydroxypyrimidine (DAHP) is considered a specific inhibitor of BH 4 biosynthesis and is widely used in order to elucidate the possible biological function of BH 4 in various cells. In the present study, we found that both the synthesis of tetrahydrobiopterin (BH 4 ) and expression of vascular cell adhesion molecule 1 (VCAM-1) were increased in human umbilical vein endothelial cells (HUVEC) treated with proinflammatory cytokines. Thus we examined the effects of DAHP to clarify whether BH 4 might be involved in the expression of VCAM-1 in HUVEC. DAHP reduced the levels of both BH 4 and VCAM-1 induced by TNF-α and IFN-γ. However, the dose-response curves of DAHP for the suppression of the VCAM-1 level and that of BH 4 level were markedly different. Supplementation with sepiapterin failed to restore the depressed VCAM-1 level, although it completely restored the BH 4 level. Furthermore, DAHP significantly reduced the VCAM-1 level under the experimental conditions using TNF-α alone, which failed to induce BH 4 production. Taken together, these results indicate that DAHP inhibited the expression of VCAM-1 in a BH 4 -independent manner in HUVEC. In the present study, we also found that DAHP significantly suppressed the accumulation of cytokine-induced NF-κB (p65) in the nucleus as well as the mRNA levels of VCAM-1 and GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme of BH 4 synthesis. The data obtained in this study suggest that DAHP reduced VCAM-1 and GTPCH protein synthesis at least partially via suppressing the NF-κB level in the nucleus of HUVEC.

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