title: Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway.
abstract: OBJECTIVE
  Adult bone marrow mononuclear cells (BMMNCs) can restore cardiac function following myocardial necrosis. Protocols used to date have administered cells relatively late after ischaemia/reperfusion injury, but there is the opportunity with elective procedures to infuse cells shortly after restoration of blood flow, for example after angioplasty. Our aim was therefore to try and quantify protection from myocardial injury by early infusion of BMMNCs in a rat ischaemia reperfusion (I/R) model.
  
  
  RESULTS
  Male Wistar rats underwent 25 min of ischaemia followed by 2 h reperfusion of the left anterior descending coronary artery. Ten million BMMNCs were injected i.v. at reperfusion. We found BMMNCs caused a significant reduction in infarct size at 2 h when assessed by staining the area at risk with p-nitro blue tetrazolium (42% reduction, P<0.01). Apoptosis and necrosis of isolated cardiomyocytes was significantly reduced in the area at risk. Functional assessment at 7 days using echocardiography and left ventricular catheterisation showed improved systolic and diastolic function in the BMMNC treatment group (LVEF: BMMNC 71 ± 3% vs. PBS 48 ± 4%, P<0.0001). In functional studies BMMNC injected animals showed increased activation of Akt, inhibition of GSK-3β, amelioration of p38 MAP kinase phosphorylation and NF-κB activity compared to control myocardium. Inhibition of PI3K with LY294002 abolished all beneficial effects of BMMNC treatment. Proteomic analysis also demonstrated that BMMNC treatment induced alterations in proteins within known cardioprotective pathways, e.g., heat shock proteins, stress-70 protein as well as the chaperone protein 14-3-3 epsilon.
  
  
  CONCLUSIONS
  Early BMMNC injection during reperfusion preserves the myocardium, with evidence of reduced apoptosis, necrosis, and activation of survival pathways.
authors.affiliation: Centre for Clinical Pharmacology, Cardiovascular Biomedical Research Unit, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lovell
authors.forename: Mohammed
authors.initials: M
authors.lastname: Yasin
authors.forename: Kate L
authors.initials: KL
authors.lastname: Lee
authors.forename: King Kenneth
authors.initials: KK
authors.lastname: Cheung
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Ahila
authors.initials: A
authors.lastname: Sivarajah
authors.forename: Kit-yi
authors.initials: KY
authors.lastname: Leung
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Amar
authors.initials: A
authors.lastname: Kapoor
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Yaqoob
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.forename: John
authors.initials: J
authors.lastname: Martin
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Munroe
authors.forename: Chris
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Anthony
authors.initials: A
authors.lastname: Mathur
mesh_terms: D017130:Angioplasty; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D016026:Bone Marrow Transplantation / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015425:Myocardial Reperfusion; D009336:Necrosis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000473:pathology; D013234:Stem Cells / Q000166:cytology
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt