Document Detail


Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway.
MedLine Citation:
PMID:  20810112     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
METHODS AND 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:
Matthew J Lovell; Mohammed Yasin; Kate L Lee; King Kenneth Cheung; Yasunori Shintani; Massimo Collino; Ahila Sivarajah; Kit-yi Leung; Kunihiko Takahashi; Amar Kapoor; Mohammed M Yaqoob; Ken Suzuki; Mark F Lythgoe; John Martin; Patricia B Munroe; Chris Thiemermann; Anthony Mathur
Publication Detail:
Type:  Journal Article     Date:  2010-08-04
Journal Detail:
Title:  Atherosclerosis     Volume:  213     ISSN:  1879-1484     ISO Abbreviation:  Atherosclerosis     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-25     Completed Date:  2011-03-07     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0242543     Medline TA:  Atherosclerosis     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  67-76     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Angioplasty
Animals
Apoptosis
Bone Marrow Cells / cytology*
Bone Marrow Transplantation / methods
Leukocytes, Mononuclear / cytology*
Male
Myocardial Infarction / pathology
Myocardial Reperfusion*
Necrosis
Phosphatidylinositol 3-Kinases / metabolism*
Proto-Oncogene Proteins c-akt / metabolism*
Rats
Rats, Wistar
Reperfusion Injury / pathology
Stem Cells / cytology
Grant Support
ID/Acronym/Agency:
G1000461//Medical Research Council; G116/158//Medical Research Council
Chemical
Reg. No./Substance:
EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt

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