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

Abstract

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
Volume91
Issue number2
DOIs
StatePublished - Jul 15 2011

Keywords

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

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia'. Together they form a unique fingerprint.

Cite this