Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway.
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.
Lovell
Matthew J
MJ
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.
Yasin
Mohammed
M
Lee
Kate L
KL
Cheung
King Kenneth
KK
Shintani
Yasunori
Y
Collino
Massimo
M
Sivarajah
Ahila
A
Leung
Kit-yi
KY
Takahashi
Kunihiko
K
Kapoor
Amar
A
Yaqoob
Mohammed M
MM
Suzuki
Ken
K
Lythgoe
Mark F
MF
Martin
John
J
Munroe
Patricia B
PB
Thiemermann
Chris
C
Mathur
Anthony
A
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
D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt