title: Cardiac-specific overexpression of GTP cyclohydrolase 1 restores ischaemic preconditioning during hyperglycaemia.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. zdge@mcw.edu
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ge
authors.forename: Irina A
authors.initials: IA
authors.lastname: Ionova
authors.forename: Nikolina
authors.initials: N
authors.lastname: Vladic
authors.forename: Danijel
authors.initials: D
authors.lastname: Pravdic
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hirata
authors.forename: Jeannette
authors.initials: J
authors.lastname: Vásquez-Vivar
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Pratt
authors.forename: David C
authors.initials: DC
authors.lastname: Warltier
authors.forename: Galen M
authors.initials: GM
authors.lastname: Pieper
authors.forename: Judy R
authors.initials: JR
authors.lastname: Kersten
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014463:Ultrasonography; D016277:Ventricular Function, Left
chemical_list: D004791:Enzyme Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D001708:Biopterins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006136:GTP Cyclohydrolase; C003402:sapropterin; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester