Apolipoprotein A-1 mimetic D-4F enhances isoflurane-induced eNOS signaling and cardioprotection during acute hyperglycemia

Ines Baotic, Zhi-Dong Ge, Filip Sedlic, Adrian Coon, Dorothee Weihrauch, David C. Warltier, Judy R. Kersten

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Acute hyperglycemia (AHG) decreases the availability of nitric oxide (NO) and impairs anesthetic preconditioning (APC)-elicited protection against myocardial infarction. We investigated whether D-4F, an apolipoprotein A-1 mimetic, rescues the myocardium by promoting APC-induced endothelial NO signaling during AHG. Myocardial infarct size was measured in mice in the absence or presence of APC [isoflurane (1.4%)] with or without AHG [dextrose (2 g/kg ip)] and D-4F (0.12 or 0.6 mg/kg ip). NO production, superoxide generation, protein compartmentalization, and posttranslational endothelial NO synthase (eNOS) modifications were assessed in human coronary artery endothelial cells cultured in 5.5 or 20 mM glucose with or without isoflurane (0.5 mM) in the presence or absence of D-4F (0.5 μg/ml). Myocardial infarct size was significantly decreased by APC (36 ± 3% of risk area) compared with control (54 ± 3%) in the absence, but not presence, of AHG (49 ± 4%). D-4F restored the cardioprotective effect of APC during AHG (36 ± 3% and 30 ± 3%, 0.12 and 0.6 mg/kg, respectively), although D-4F alone had no effect on infarct size (53 ± 3%). Isoflurane promoted caveolin-1 and eNOS compartmentalization within endothelial cell caveolae and eNOS dimerization, concomitant with increased NO production (411 ± 28 vs. 68 ± 10 pmol/mg protein in control). These actions were attenuated by AHG (NO production: 264 ± 18 pmol/mg protein). D-4F reduced superoxide generation and enhanced caveolin-1 and eNOS caveolar compartmentalization and posttranslational eNOS modifications, thus restoring NO production during isoflurane and AHG (418 ± 36 pmol/mg protein). In conclusion, D-4F restored the cardioprotective effect of APC during AHG, possibly by decreasing superoxide generation, which promoted isoflurane-induced eNOS signaling and NO biosynthesis.

Original languageEnglish (US)
Pages (from-to)H219-H227
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume305
Issue number2
DOIs
StatePublished - Jul 15 2013

Keywords

  • Anesthetic preconditioning
  • Cardioprotection
  • D-4F
  • Endothelial nitric oxide synthase
  • Hyperglycemia
  • Nitric oxide

ASJC Scopus subject areas

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

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