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Thromb Haemost 2015; 113(03): 513-521
DOI: 10.1160/TH14-07-0592
Theme Issue Article
Schattauer GmbH

Akt protects the heart against ischaemia-reperfusion injury by modulating mitochondrial morphology

Sang-Bing Ong
1   The Hatter Cardiovascular Institute,University College London Hospital, London, UK
,
Andrew R. Hall
1   The Hatter Cardiovascular Institute,University College London Hospital, London, UK
,
Rachel K. Dongworth
1   The Hatter Cardiovascular Institute,University College London Hospital, London, UK
,
Siavash Kalkhoran
1   The Hatter Cardiovascular Institute,University College London Hospital, London, UK
,
Aswin Pyakurel
2   Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy
,
Luca Scorrano
2   Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Padua, Italy
,
Derek J. Hausenloy
1   The Hatter Cardiovascular Institute,University College London Hospital, London, UK
› Author Affiliations Financial support: Dr. Sang-Bing Ong was funded by a Dorothy Hodgkin Postgraduate Award (Biotechnology and Biological Sciences Research Council). Dr. Derek J Hausenloy is funded by a British Heart Foundation Senior Clinical Research Fellowship (FS/10/039/28270). This work was undertaken at University College London Hospital/University College London who received a proportion of funding from the Department of Health’s National Institute of Health Research Biomedical Research Centres funding scheme.
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Publication History

Received: 10 July 2014

Accepted after major revision: 15 August 2014

Publication Date:
17 November 2017 (online)

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Summary

The mechanism through which the protein kinase Akt (also called PKB), protects the heart against acute ischaemia-reperfusion injury (IRI) is not clear. Here, we investigate whether Akt mediates its cardioprotective effect by modulating mitochondrial morphology. Transfection of HL-1 cardiac cells with constitutively active Akt (caAkt) changed mitochondrial morphology as evidenced by an increase in the proportion of cells displaying predominantly elongated mitochondria (73 ± 5.0 % caAkt vs 49 ± 5.8 % control: N=80 cells/group; p< 0.05). This effect was associated with delayed time taken to induce mitochondrial permeability transition pore (MPTP) opening (by 2.4 ± 0.5 fold; N=80 cells/group: p< 0.05); and reduced cell death following simulated IRI (32.8 ± 1.2 % caAkt vs 63.8 ± 5.6 % control: N=320 cells/group: p< 0.05). Similar effects on mitochondrial morphology, MPTP opening, and cell survival post-IRI, were demonstrated with pharmacological activation of Akt using the known cardioprotective cytokine, erythropoietin (EPO). The effect of Akt on inducing mitochondrial elongation was found to be dependent on the mitochondrial fusion protein, Mitofusin-1 (Mfn1), as ablation of Mfn1 in mouse embryonic fibroblasts (MEFs) abrogated Akt-mediated mitochondrial elongation. Finally, in vivo pre-treatment with EPO reduced myocardial infarct size (as a % of the area at risk) in adult mice subjected to IRI (26.2 ± 2.6 % with EPO vs 46.1 ± 6.5 % in control; N=7/group: p< 0.05), and reduced the proportion of cells displaying myofibrillar disarray and mitochondrial fragmentation observed by electron microscopy in adult murine hearts subjected to ischaemia from 5.8 ± 1.0 % to 2.2 ± 1.0 % (N=5 hearts/group; p< 0.05). In conclusion, we found that either genetic or pharmacological activation of Akt protected the heart against acute ischaemia-reperfusion injury by modulating mitochondrial morphology.

Keywords

Ischaemia - reperfusion - myocardial infarction - mitochondrial morphology - Akt
 

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