Induction of tetrahydrobiopterin synthesis in rat cardiac myocytes: impact on cytokine-induced NO generation. 1997

K Kasai, and Y Hattori, and N Banba, and S Hattori, and S Motohashi, and S Shimoda, and N Nakanishi, and S S Gross
Department of Endocrinology, Dokkyo University School of Medicine, Tochigi, Japan.

Because tetra-hydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) formation, we investigated whether BH4 synthesis is required for cytokine-induced NO production in cultured rat cardiac myocytes. The total biopterin content of untreated cardiac myocytes was below our limit of detection. However, treatment with interleukin-1 alpha (IL-1 alpha) + interferon-gamma (IFN-gamma) caused a significant rise in biopterin levels and induced NO synthesis. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTP cyclohydrolase I (the rate-limiting enzyme for de novo BH4 synthesis), completely abolished the elevation in biopterin levels induced by IL-1 alpha + IFN-gamma. DAHP also caused a concentration-dependent inhibition of (IL-1 alpha + IFN-gamma)-induced NO synthesis. Similarly, N-acetylserotonin, an inhibitor of the BH4 synthetic enzyme sepiapterin reductase, blocked increases in biopterin levels as well as NO synthesis induced by IL-1 alpha + IFN-gamma. Sepiapterin, substrate for BH4 synthesis via the pterin salvage pathway, prevented this inhibition by DAHP or N-acetylserotonin, and this effect was blocked by methotrexate. Sepiapterin and, to a lesser extent, BH4 dose dependently enhanced (IL-1 alpha + IFN-gamma)-induced NO synthesis, suggesting that the concentration of BH4 limits the rate of NO production. Inducible NO synthase mRNA and GTP cyclohydrolase I mRNA were induced by IL-1 alpha + IFN-gamma in parallel. We thus demonstrate that BH4 synthesis is an absolute requirement for induction of NO synthesis by cytokines in cardiac myocytes.

UI MeSH Term Description Entries
D007371 Interferon-gamma The major interferon produced by mitogenically or antigenically stimulated LYMPHOCYTES. It is structurally different from TYPE I INTERFERON and its major activity is immunoregulation. It has been implicated in the expression of CLASS II HISTOCOMPATIBILITY ANTIGENS in cells that do not normally produce them, leading to AUTOIMMUNE DISEASES. Interferon Type II,Interferon, Immune,gamma-Interferon,Interferon, gamma,Type II Interferon,Immune Interferon,Interferon, Type II
D007375 Interleukin-1 A soluble factor produced by MONOCYTES; MACROPHAGES, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. Interleukin-1 is a general term refers to either of the two distinct proteins, INTERLEUKIN-1ALPHA and INTERLEUKIN-1BETA. The biological effects of IL-1 include the ability to replace macrophage requirements for T-cell activation. IL-1,Lymphocyte-Activating Factor,Epidermal Cell Derived Thymocyte-Activating Factor,Interleukin I,Macrophage Cell Factor,T Helper Factor,Epidermal Cell Derived Thymocyte Activating Factor,Interleukin 1,Lymphocyte Activating Factor
D009206 Myocardium The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow. Muscle, Cardiac,Muscle, Heart,Cardiac Muscle,Myocardia,Cardiac Muscles,Heart Muscle,Heart Muscles,Muscles, Cardiac,Muscles, Heart
D009569 Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP. Endogenous Nitrate Vasodilator,Mononitrogen Monoxide,Nitric Oxide, Endothelium-Derived,Nitrogen Monoxide,Endothelium-Derived Nitric Oxide,Monoxide, Mononitrogen,Monoxide, Nitrogen,Nitrate Vasodilator, Endogenous,Nitric Oxide, Endothelium Derived,Oxide, Nitric,Vasodilator, Endogenous Nitrate
D004338 Drug Combinations Single preparations containing two or more active agents, for the purpose of their concurrent administration as a fixed dose mixture. Drug Combination,Combination, Drug,Combinations, Drug
D004790 Enzyme Induction An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. Induction, Enzyme
D006136 GTP Cyclohydrolase (GTP cyclohydrolase I) or GTP 7,8-8,9-dihydrolase (pyrophosphate-forming) (GTP cyclohydrolase II). An enzyme group that hydrolyzes the imidazole ring of GTP, releasing carbon-8 as formate. Two C-N bonds are hydrolyzed and the pentase unit is isomerized. This is the first step in the synthesis of folic acid from GTP. EC 3.5.4.16 (GTP cyclohydrolase I) and EC 3.5.4.25 (GTP cyclohydrolase II). GTP 8-Formylhydrolase,GTP Dihydrolase,GTP Ring-Opening Enzyme,7,8-Dihydroneopterintriphosphate Synthetase,GTP Cyclohydrolase I,GTP Cyclohydrolase II,7,8 Dihydroneopterintriphosphate Synthetase,8-Formylhydrolase, GTP,Cyclohydrolase I, GTP,Cyclohydrolase II, GTP,Cyclohydrolase, GTP,Dihydrolase, GTP,GTP 8 Formylhydrolase,GTP Ring Opening Enzyme,Ring-Opening Enzyme, GTP,Synthetase, 7,8-Dihydroneopterintriphosphate
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001708 Biopterins Pterin derivatives based on 2-amino-6-(1,2-dihydroxypropyl)-4(1H)-pteridinone. Biopterins are natural products that have been considered as growth factors for some insects. Biopterins are cofactors for the AROMATIC AMINO ACID hydroxylases and NITRIC OXIDE SYNTHASE. Deficiencies in BIOPTERINS metabolism (e.g., lowered TETRAHYDROBIOPTERIN) are associated with neurological deterioration (e.g., HYPERPHENYLALANINAEMIA). 2-Amino-6-((1S,2R)-1,2-dihydroxypropyl)-4(1H)-pteridinone,2-Amino-6-((1S,2S)-1,2-dihydroxypropyl)-4(1H)-pteridinone,2-Amino-6-(1,2-dihydroxypropyl)-4(8H)-pteridinone,2-amino-6-((1R,2R)-1,2-dihydroxypropyl)-4(3H)-pteridinone,4(1H)-Pteridinone, 2-amino-6-(1,2-dihydroxypropyl)-, (S-(R*,S*))-,6-Biopterin,Biopterin,D-threo-Biopterin,L-Biopterin,L-erythro-Biopterin,L-threo-Biopterin,2-Amino-6-(1,2-dihydroxypropyl)-4(1H)-pteridinone,Dictyopterin,Orinapterin,6 Biopterin,D threo Biopterin,L Biopterin,L erythro Biopterin,L threo Biopterin
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated

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