title: Apolipoprotein A-1 mimetic D-4F enhances isoflurane-induced eNOS signaling and cardioprotection during acute hyperglycemia.
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.
authors.affiliation: Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Baotic
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Ge
authors.forename: Filip
authors.initials: F
authors.lastname: Sedlic
authors.forename: Adrian
authors.initials: A
authors.lastname: Coon
authors.forename: Dorothee
authors.initials: D
authors.lastname: Weihrauch
authors.forename: David C
authors.initials: DC
authors.lastname: Warltier
authors.forename: Judy R
authors.initials: JR
authors.lastname: Kersten
mesh_terms: D000208:Acute Disease; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005947:Glucose; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000139:chemically induced / Q000150:complications* / Q000201:enzymology; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015425:Myocardial Reperfusion / Q000009:adverse effects*; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
chemical_list: D016632:Apolipoprotein A-I; D001786:Blood Glucose; C495540:CAV1 protein, human; D051242:Caveolin 1; C465468:D-4F peptide; D013481:Superoxides; D009569:Nitric Oxide; D007530:Isoflurane; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D005947:Glucose
keywords: D-4F; anesthetic preconditioning; cardioprotection; endothelial nitric oxide synthase; hyperglycemia; nitric oxide