title: Intralipid protects the heart in late pregnancy against ischemia/reperfusion injury via Caveolin2/STAT3/GSK-3β pathway.
abstract: We recently demonstrated that the heart of late pregnant (LP) rodents is more prone to ischemia/reperfusion (I/R) injury compared to non-pregnant rodents. Lipids, particularly polyunsaturated fatty acids, have received special attention in the field of cardiovascular research. Here, we explored whether Intralipid (ITLD) protects the heart against I/R injury in LP rodents and investigated the mechanisms underlying this protection.
  
  
  
  In-vivo female LP rat hearts or ex-vivo isolated Langendorff-perfused LP mouse hearts were subjected to ischemia followed by reperfusion with PBS or ITLD (one bolus of 5mg/kg of 20% in in-vivo and 1% in ex-vivo). Myocardial infarct size, mitochondrial calcium retention capacity, genome-wide expression profiling, pharmacological inhibition and co-immunoprecipitation were performed. One bolus of ITLD at reperfusion significantly reduced the in-vivo myocardial infarct size in LP rats (23.3±2% vs. 55.5±3.4% in CTRL, p<0.01). Postischemic administration of ITLD also protected the LP hearts against I/R injury ex-vivo. ITLD significantly increased the threshold for the opening of the mitochondrial permeability transition pore in response to calcium overload (nmol-calcium/mg-mitochondrial protein: 290±17 vs. 167±10 in CTRL, p<0.01) and significantly increased phosphorylation of STAT3 (1.8±0.08 vs. 1±0.16 in CTRL, p<0.05) and GSK-3β (2.63±0.55 vs. 1±0.0.34 in CTRL, p<0.05). The ITLD-induced cardioprotection was fully abolished by Stattic, a specific inhibitor of STAT3. Transcriptome analysis revealed caveolin 2 (Cav2) was significantly upregulated by ITLD in hearts of LP rats under I/R injury. Co-immunoprecipitation experiments showed that Cav2 interacts with STAT3.
  
  
  
  ITLD protects the heart in late pregnancy against I/R injury by inhibiting the mPTP opening through Cav2/STAT3/GSK-3β pathway.
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Ruffenach
authors.affiliation: Institute of Gender in Medicine, Center for Cardiovascular Research, Charite University Hospital, Germany; DZHK (German Centre for Cardiovascular Research), Berlin Partner Site, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Cunningham
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States.
authors.forename: Negar
authors.initials: N
authors.lastname: Motayagheni
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States.
authors.forename: Neusha
authors.initials: N
authors.lastname: Barakai
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States.
authors.forename: Soban
authors.initials: S
authors.lastname: Umar
authors.affiliation: Institute of Gender in Medicine, Center for Cardiovascular Research, Charite University Hospital, Germany; DZHK (German Centre for Cardiovascular Research), Berlin Partner Site, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.affiliation: Department of Anesthesiology, Division of Molecular Medicine, Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1778, United States. Electronic address: meghbali@ucla.edu.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Eghbali
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D051243:Caveolin 2 / Q000378:metabolism*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004655:Emulsions / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D010539:Permeability; D010743:Phospholipids / Q000008:administration & dosage / Q000494:pharmacology*; D010766:Phosphorylation; D011247:Pregnancy; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013024:Soybean Oil / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D059467:Transcriptome
chemical_list: D051243:Caveolin 2; D004655:Emulsions; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010743:Phospholipids; D020011:Protective Agents; D050796:STAT3 Transcription Factor; C545823:soybean oil, phospholipid emulsion; D013024:Soybean Oil; D000071679:Glycogen Synthase Kinase 3 beta; D002118:Calcium
keywords: Caveolin-2; Intralipid; Ischemia/reperfusion; Pregnancy; STAT3; mPTP