Document Detail

Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia.
MedLine Citation:
PMID:  21422102     Owner:  NLM     Status:  MEDLINE    
AIMS: Hyperglycaemia (HG) decreases intracellular tetrahydrobiopterin (BH(4)) concentrations, and this action may contribute to injury during myocardial ischaemia and reperfusion. We investigated whether increased BH(4) by cardiomyocyte-specific overexpression of the GTP cyclohydrolase (GTPCH) 1 gene rescues myocardial and mitochondrial protection by ischaemic preconditioning (IPC) during HG through a nitric oxide (NO)-dependent pathway.
METHODS AND RESULTS: Mice underwent 30 min of myocardial ischaemia followed by 2 h of reperfusion with or without IPC elicited with four cycles of 5 min ischaemia/5 min of reperfusion in the presence or absence of HG produced by d-glucose. In C57BL/6 wild-type mice, IPC increased myocardial BH(4) and NO concentrations and decreased myocardial infarct size (30 ± 3% of risk area) compared with control (56 ± 5%) experiments. This protective effect was inhibited by HG (48 ± 3%) but not hyperosmolarity. GTPCH-1 overexpression increased myocardial BH(4) and NO concentrations and restored cardioprotection by IPC during HG (32 ± 4%). In contrast, a non-selective NO synthase inhibitor N(G)-nitro-l-arginine methyl ester attenuated the favourable effects of GTPCH-1 overexpression (52 ± 3%) during HG. Mitochondria isolated from myocardium subjected to IPC required significantly higher in vitro Ca(2+) concentrations (184 ± 14 µmol mg(-1) protein) to open the mitochondrial permeability transition pore when compared with mitochondria isolated from control experiments (142 ± 10 µmol mg(-1) protein). This beneficial effect of IPC was reversed by HG and rescued by GTPCH-1 overexpression.
CONCLUSION: Increased BH(4) by cardiomyocyte-specific overexpression of GTPCH-1 preserves the ability of IPC to elicit myocardial and mitochondrial protection that is impaired by HG, and this action appears to be dependent on NO.
Zhi-Dong Ge; Irina A Ionova; Nikolina Vladic; Danijel Pravdic; Naoyuki Hirata; Jeannette Vásquez-Vivar; Phillip F Pratt; David C Warltier; Galen M Pieper; Judy R Kersten
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-03-21
Journal Detail:
Title:  Cardiovascular research     Volume:  91     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-29     Completed Date:  2011-10-28     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  340-9     Citation Subset:  IM    
Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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MeSH Terms
Analysis of Variance
Biopterin / analogs & derivatives,  metabolism
Calcium / metabolism
Disease Models, Animal
Enzyme Inhibitors / pharmacology
GTP Cyclohydrolase / genetics,  metabolism*
Hyperglycemia / complications*,  enzymology,  genetics
Ischemic Preconditioning, Myocardial*
Mice, Inbred C57BL
Mitochondria, Heart / drug effects,  enzymology*,  pathology
Mitochondrial Membrane Transport Proteins / metabolism
Myocardial Infarction / enzymology,  genetics,  physiopathology,  prevention & control*,  ultrasonography
Myocardial Reperfusion Injury / enzymology,  genetics,  physiopathology,  prevention & control*,  ultrasonography
Myocardium / enzymology*,  pathology
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide / metabolism
Nitric Oxide Synthase / antagonists & inhibitors,  metabolism
Signal Transduction
Time Factors
Ventricular Function, Left
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Mitochondrial Membrane Transport Proteins; 0/mitochondrial permeability transition pore; 10102-43-9/Nitric Oxide; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 50903-99-6/NG-Nitroarginine Methyl Ester; 7440-70-2/Calcium; EC Oxide Synthase; EC Cyclohydrolase

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

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