Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway

Lovell, Matthew J.; Yasin, Mohammed; Lee, Kate L.; Cheung, King Kenneth; Shintani, Yasunori; Collino, Massimo; Sivarajah, Ahila; Leung, Kit-yi; Takahashi, Kunihiko; Kapoor, Amar; Yaqoob, Mohammed M.; Suzuki, Ken; Lythgoe, Mark F.; Martin, John; Munroe, Patricia B.; Thiemermann, Chris; Mathur, Anthony

doi:10.1016/j.atherosclerosis.2010.07.045

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Volume 213, Issue 1 , Pages 67-76, November 2010

Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway

Matthew J. Lovell
- 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
- These authors have contributed equally and are joint first authors of this article.
Mohammed Yasin
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
- These authors have contributed equally and are joint first authors of this article.
Kate L. Lee
- 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
King Kenneth Cheung
- Centre for Advanced Biomedical Imaging, Department of Medicine and Institute of Child Health, University College London, London WC1E 6DD, UK
- Department of Medical Physics and Bioengineering, University College London, London WC1E 6DD, UK
Yasunori Shintani
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Massimo Collino
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Ahila Sivarajah
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Kit-yi Leung
- 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
Kunihiko Takahashi
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Amar Kapoor
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Mohammed M. Yaqoob
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Ken Suzuki
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
Mark F. Lythgoe
- Centre for Advanced Biomedical Imaging, Department of Medicine and Institute of Child Health, University College London, London WC1E 6DD, UK
John Martin
- British Heart Foundation Laboratories, Department of Medicine, University College London, London WC1E 6JJ, UK
Patricia B. Munroe
- 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
Chris Thiemermann
- Centre for Translational Medicine & Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
- These authors have contributed equally and are joint last authors of this article.
Anthony Mathur
- 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
- These authors have contributed equally and are joint last authors of this article.
- Corresponding author. Tel.: +44 208 983 2216; fax: +44 208 983 2381.

Received 13 January 2010; received in revised form 22 July 2010; accepted 23 July 2010. published online 01 September 2010.

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.

Methods and results

Male Wistar rats underwent 25min of ischaemia followed by 2h 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 2h 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.