title: Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury.
abstract: BACKGROUND
  Intralipid (Sigma, St. Louis, MO), a brand name for the first safe fat emulsion for human use, has been shown to be cardioprotective. However, the mechanism of this protection is not known. The authors investigated the molecular mechanism(s) of Intralipid-induced cardioprotection against ischemia/reperfusion injury, particularly the role of glycogen synthase kinase-3β (GSK-3β) and mitochondrial permeability transition pore in this protective action.
  
  
  METHODS
  In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with Intralipid (1% in ex vivo and one bolus of 20% in in vivo) or vehicle. The hemodynamic function, infarct size, threshold for the opening of mitochondrial permeability transition pore, and phosphorylation levels of protein kinase B (Akt)/extracellular signal regulating kinase (ERK)/GSK-3β were measured.
  
  
  RESULTS
  Administration of Intralipid at the onset of reperfusion resulted in approximately 70% reduction in infarct size in the in vivo rat model. Intralipid also significantly improved functional recovery of isolated Langendorff-perfused mouse hearts as the rate pressure product was increased from 2,999 ± 863 mmHg*beats/min in the control group to 13,676 ± 611 mmHg*beats/min (mean±SEM) and the infarct size was markedly smaller (18.3 ± 2.4% vs. 54.8 ± 2.9% in the control group, P < 0.01). The Intralipid-induced cardioprotection was fully abolished by LY294002, a specific inhibitor of PI3K, but only partially by PD98059, a specific ERK inhibitor. Intralipid also increased the phosphorylation levels of Akt/ERK1/glycogen synthase kinase-3β by eightfold, threefold, and ninefold, respectively. The opening of mitochondrial permeability transition pore was inhibited by Intralipid because calcium retention capacity was higher in the Intralipid group (274.3 ± 8.4 nM/mg vs. 168.6 ± 9.6 nM/mg in the control group).
  
  
  CONCLUSIONS
  Postischemic treatment with Intralipid inhibits the opening of mitochondiral permeability transition pore and protects the heart through glycogen synthase kinase-3β via PI3K/Akt/ERK pathways.
authors.affiliation: David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Siamak
authors.initials: S
authors.lastname: Rahman
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Li
authors.forename: Jean Chrisostome
authors.initials: JC
authors.lastname: Bopassa
authors.forename: Soban
authors.initials: S
authors.lastname: Umar
authors.forename: Andrea
authors.initials: A
authors.lastname: Iorga
authors.forename: Parisa
authors.initials: P
authors.lastname: Partownavid
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004655:Emulsions / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D057775:Ischemic Postconditioning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids / Q000627:therapeutic use; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013024:Soybean Oil / Q000627:therapeutic use
chemical_list: D002118:Calcium; D002867:Chromones; D004655:Emulsions; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010743:Phospholipids; D013024:Soybean Oil; C545823:soybean oil, phospholipid emulsion; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one