Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


AimsHyperglycaemia (HG) decreases intracellular tetrahydrobiopterin (BH4) concentrations, and this action may contribute to injury during myocardial ischaemia and reperfusion. We investigated whether increased BH4 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 resultsMice 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 BH4 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 BH4 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 mol mg-1 protein) to open the mitochondrial permeability transition pore when compared with mitochondria isolated from control experiments (142 ± 10 mol mg -1 protein). This beneficial effect of IPC was reversed by HG and rescued by GTPCH-1 overexpression.ConclusionIncreased BH4 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.

Original languageEnglish (US)
Pages (from-to)340-349
Number of pages10
JournalCardiovascular research
Issue number2
StatePublished - Jul 15 2011


  • GTP cyclohydrolase 1
  • Gene transfer
  • Hyperglycaemia
  • Ischemia reperfusion
  • Mitochondria

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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