Document Detail


Cardiomyocyte GTP cyclohydrolase 1 and tetrahydrobiopterin increase NOS1 activity and accelerate myocardial relaxation.
MedLine Citation:
PMID:  22798524     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOS). Oral BH4 supplementation preserves cardiac function in animal models of cardiac disease; however, the mechanisms underlying these findings are not completely understood.
OBJECTIVE: To study the effect of myocardial transgenic overexpression of the rate-limiting enzyme in BH4 biosynthesis, GTP cyclohydrolase 1 (GCH1), on NOS activity, myocardial function, and Ca2+ handling.
METHODS AND RESULTS: GCH1overexpression significantly increased the biopterins level in left ventricular (LV) myocytes but not in the nonmyocyte component of the LV myocardium or in plasma. The ratio between BH4 and its oxidized products was lower in mGCH1-Tg, indicating that a large proportion of the myocardial biopterin pool was oxidized; nevertheless, myocardial NOS1 activity was increased in mGCH1-Tg, and superoxide release was significantly reduced. Isolated hearts and field-stimulated LV myocytes (3 Hz, 35°C) overexpressing GCH1 showed a faster relaxation and a PKA-mediated increase in the PLB Ser16 phosphorylated fraction and in the rate of decay of the [Ca2+]i transient. RyR2 S-nitrosylation and diastolic Ca2+ leak were larger in mGCH1-Tg and ICa density was lower; nevertheless the amplitude of the [Ca2+]i transient and contraction did not differ between genotypes, because of an increase in the SR fractional release of Ca2+ in mGCH1-Tg myocytes. Xanthine oxidoreductase inhibition abolished the difference in superoxide production but did not affect myocardial function in either group. By contrast, NOS1 inhibition abolished the differences in ICa density, Ser16 PLB phosphorylation, [Ca2+]i decay, and myocardial relaxation between genotypes.
CONCLUSIONS: Myocardial GCH1 activity and intracellular BH4 are a limiting factor for constitutive NOS1 and SERCA2A activity in the healthy myocardium. Our findings suggest that GCH1 may be a valuable target for the treatment of LV diastolic dysfunction.
Authors:
Ricardo Carnicer; Ashley B Hale; Silvia Suffredini; Xing Liu; Svetlana Reilly; Mei Hua Zhang; Nicoletta C Surdo; Jennifer K Bendall; Mark J Crabtree; Gregory B S Lim; Nicholas J Alp; Keith M Channon; Barbara Casadei
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-12
Journal Detail:
Title:  Circulation research     Volume:  111     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-31     Completed Date:  2012-11-30     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  718-27     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Biopterin / analogs & derivatives*,  metabolism,  pharmacology
Calcium / metabolism
Cells, Cultured
Enzyme Activation / drug effects
Female
GTP Cyclohydrolase / genetics,  metabolism*
Heart / drug effects,  physiology
Humans
Immunoblotting
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Transgenic
Myocardium / cytology,  enzymology
Myocytes, Cardiac / enzymology
Nitric Oxide Synthase Type I / metabolism*
Ryanodine Receptor Calcium Release Channel / metabolism
Sarcoplasmic Reticulum / metabolism
Superoxides / metabolism
Grant Support
ID/Acronym/Agency:
090532//Wellcome Trust; RG/11/15/29375//British Heart Foundation; RG/12/5/29576//British Heart Foundation; //British Heart Foundation; //Medical Research Council
Chemical
Reg. No./Substance:
0/Ryanodine Receptor Calcium Release Channel; 11062-77-4/Superoxides; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; EC 1.14.13.39/Nitric Oxide Synthase Type I; EC 3.5.4.16/GTP Cyclohydrolase; SY7Q814VUP/Calcium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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