title: Acute hyperglycemia abolishes ischemic preconditioning by inhibiting Akt phosphorylation: normalizing blood glucose before ischemia restores ischemic preconditioning.
abstract: This study examined the hypothesis that acute hyperglycemia (HG) blocks ischemic preconditioning (IPC) by inhibiting Akt phosphorylation. Brief HG of approximately 400 mg/dL was induced in C57BL/6 mice via intraperitoneal injection of 20% dextrose (2 g/kg). All mice underwent 40 min LAD occlusion and 60 min reperfusion. The IPC protocol was 2 cycles of 5 min ischemia and 5 min reperfusion prior to index ischemia.
  
  
  RESULTS
  In control mice, infarct size (IF) was 51.7 ± 2.0 (% risk region). Preconditioning reduced IF by 50% to 25.8 ± 3.2 (P < 0.05 versus control). In HG mice, IF was significantly exacerbated to 58.1 ± 2.3. However, the effect of IPC completely disappeared in HG mice. Normalization of blood glucose with insulin 5 min before IPC recovered the cardioprotective effect. Administration of CCPA before index ischemia mimicked IPC effect. The cardioprotective effect of CCPA, not its chronotropic effect, completely disappeared in HG mice. Phosphorylation of cardiac tissue Akt before index ischemia was enhanced by IPC or CCPA but was significantly inhibited by HG in both groups. Normalization of glucose with insulin reversed the inhibition of Akt phosphorylation by HG.
  
  
  CONCLUSIONS
  HG abolishes the cardioprotective effect of preconditioning by inhibiting Akt phosphorylation. Normalization of blood glucose with insulin suffices to recover the cardioprotective effect of preconditioning.
authors.affiliation: Department of Surgery, University of Virginia Health System, P.O. Box 800709, Charlottesville, VA 22908, USA ; Department of Biomedical Engineering, University of Virginia Health System, P.O. Box 800759, Charlottesville, VA 22908, USA.
authors.forename: Zequan
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Surgery, University of Virginia Health System, P.O. Box 800709, Charlottesville, VA 22908, USA.
authors.forename: Yikui
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of Surgery, University of Virginia Health System, P.O. Box 800709, Charlottesville, VA 22908, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Virginia Health System, P.O. Box 800709, Charlottesville, VA 22908, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Hennessy
authors.affiliation: Department of Surgery, University of Virginia Health System, P.O. Box 800709, Charlottesville, VA 22908, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.affiliation: Department of Biomedical Engineering, University of Virginia Health System, P.O. Box 800759, Charlottesville, VA 22908, USA.
authors.forename: Brent A
authors.initials: BA
authors.lastname: French
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006943:Hyperglycemia / Q000097:blood* / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D019157:Ischemic Preconditioning, Myocardial; D051379:Mice; D008810:Mice, Inbred C57BL; D017202:Myocardial Ischemia / Q000097:blood* / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D007328:Insulin; D058906:Purinergic P1 Receptor Agonists; D051057:Proto-Oncogene Proteins c-akt