| Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia. | |
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MedLine Citation:
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PMID: 21422102 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-03-21 |
Journal Detail:
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Title: Cardiovascular research Volume: 91 ISSN: 1755-3245 ISO Abbreviation: Cardiovasc. Res. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-29 Completed Date: 2011-10-28 Revised Date: 2012-09-20 |
Medline Journal Info:
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Nlm Unique ID: 0077427 Medline TA: Cardiovasc Res Country: England |
Other Details:
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Languages: eng Pagination: 340-9 Citation Subset: IM |
Affiliation:
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Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. zdge@mcw.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Analysis of Variance Animals Biopterin / analogs & derivatives, metabolism Calcium / metabolism Disease Models, Animal Enzyme Inhibitors / pharmacology GTP Cyclohydrolase / genetics, metabolism* Humans Hyperglycemia / complications*, enzymology, genetics Ischemic Preconditioning, Myocardial* Mice 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 | |
ID/Acronym/Agency:
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GM 066730/GM/NIGMS NIH HHS; HL 054820/HL/NHLBI NIH HHS; HL 063705/HL/NHLBI NIH HHS; HL 079837/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 1.14.13.39/Nitric Oxide Synthase; EC 3.5.4.16/GTP Cyclohydrolase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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