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Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia. Cardiovasc Res 2011 Jul 15;91(2):340-9 PMID: 21422102 PMCID: PMC3125073

Pubmed ID

21422102

DOI

10.1093/cvr/cvr079

Abstract

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.

Author List

Ge ZD, Ionova IA, Vladic N, Pravdic D, Hirata N, Vásquez-Vivar J, Pratt PF Jr, Warltier DC, Pieper GM, Kersten JR

Author

Jeannette M. Vasquez-Vivar PhD Professor in the Biophysics department at Medical College of Wisconsin

Scopus

2-s2.0-79960007388   17 Citations

MESH terms used to index this publication - Major topics in bold

Analysis of Variance
Animals
Biopterin
Calcium
Disease Models, Animal
Enzyme Inhibitors
GTP Cyclohydrolase
Humans
Hyperglycemia
Ischemic Preconditioning, Myocardial
Mice
Mice, Inbred C57BL
Mitochondria, Heart
Mitochondrial Membrane Transport Proteins
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardium
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
Signal Transduction
Time Factors
Ultrasonography
Ventricular Function, Left