Skip Navigation

Cardiovascular Research 2003 60(3):617-625; doi:10.1016/j.cardiores.2003.09.025
© 2003 by European Society of Cardiology
This Article
Right arrow Full Text Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Hausenloy, D. J
Right arrow Articles by Yellon, D. M
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hausenloy, D. J
Right arrow Articles by Yellon, D. M
Social Bookmarking
 Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2003, European Society of Cardiology

Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia–reperfusion injury

Derek J Hausenloya, Michael R Duchenb and Derek M Yellon*,a

aThe Hatter Institute and Centre for Cardiology, University College London Hospitals and Medical School, Grafton Way, London, WC1E 6DB, UK
bThe Mitochondrial Biology Group, Department of Physiology, University College London, London, WC1E 6BT, UK

*Corresponding author. Tel.: +44-207-380-9776; fax: +44-207-388-5095. Email address: hatter-institute{at}ucl.ac.uk

Objective: The opening of the mitochondrial permeability transition pore (mPTP) in the first few minutes of post-ischaemic reperfusion is a critical determinant of reperfusion-induced cell death. We hypothesised that the novel immunosuppressant, sanglifehrin-A (SFA), given at the time of reperfusion, protects the myocardium from ischaemia–reperfusion injury, by suppressing mPTP opening. Methods: Isolated perfused rat hearts were subjected to 35 min ischaemia/120 min reperfusion, and were treated with (1) SFA (1.0 µM) or (2) DMSO vehicle for the first 15 min of reperfusion or (3) SFA (1.0 µM) after the first 15 min of reperfusion. We examined the effect of SFA on mPTP opening directly, using a myocyte model of oxidative stress. Laser illumination of adult rat myocytes loaded with the fluorophore, TMRM, generates oxidative stress, which induces mPTP opening (represented by mitochondrial membrane depolarisation) followed by rigour contracture. Results: In the isolated perfused heart model, SFA, given during the first 15 min of post-ischaemic reperfusion, reduced the infarct-risk volume ratio from 43.9±2.5% in the control group to 23.8±4.2% with SFA (p = 0.001). However, when SFA was given after the first 15 min of reperfusion, there was no change in infarct size (43.8±5.7% with SFA vs. 43.9±2.5% in control; p = NS), suggesting that SFA has to be present during the first 15 min of reperfusion to induce protection. In the isolated adult myocyte model, SFA was shown to inhibit mPTP opening in the setting of oxidative stress, represented by an increase in the ROS threshold required to induce: mitochondrial membrane depolarisation (from 269±21 to 777±100 s; p<0.001) and rigour contracture (from 613±14 to 1329±129 s; p<0.001). Conclusions: Inhibiting mPTP opening during the first few minutes of reperfusion, using sanglifehrin-A, limits infarct size and protects myocytes from oxidative stress.

KEYWORDS Infarction; Ischaemia; Membrane permeability; Membrane potential; Reperfusion


Time for primary review 24 days


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
Cardiovasc ResHome page
J. Inserte, J. A. Barrabes, V. Hernando, and D. Garcia-Dorado
Orphan targets for reperfusion injury
Cardiovasc Res, July 15, 2009; 83(2): 169 - 178.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
A. Granfeldt, D. J. Lefer, and J. Vinten-Johansen
Protective ischaemia in patients: preconditioning and postconditioning
Cardiovasc Res, July 15, 2009; 83(2): 234 - 246.
[Abstract] [Full Text] [PDF]


Home page
Anesth. Analg.Home page
P. S. Pagel and J. G. Krolikowski
Transient Metabolic Alkalosis During Early Reperfusion Abolishes Helium Preconditioning Against Myocardial Infarction: Restoration of Cardioprotection by Cyclosporin A in Rabbits
Anesth. Analg., April 1, 2009; 108(4): 1076 - 1082.
[Abstract] [Full Text] [PDF]


Home page
Am. J. Physiol. Gastrointest. Liver Physiol.Home page
Z. Zhong, V. K. Ramshesh, H. Rehman, R. T. Currin, V. Sridharan, T. P. Theruvath, I. Kim, G. L. Wright, and J. J. Lemasters
Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion
Am J Physiol Gastrointest Liver Physiol, October 1, 2008; 295(4): G823 - G832.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
H. Kobayashi, S. Minatoguchi, S. Yasuda, N. Bao, I. Kawamura, M. Iwasa, T. Yamaki, S. Sumi, Y. Misao, H. Ushikoshi, et al.
Post-infarct treatment with an erythropoietin-gelatin hydrogel drug delivery system for cardiac repair
Cardiovasc Res, September 1, 2008; 79(4): 611 - 620.
[Abstract] [Full Text] [PDF]


Home page
NEJMHome page
D. J. Hausenloy and D. M. Yellon
Time to Take Myocardial Reperfusion Injury Seriously
N. Engl. J. Med., July 31, 2008; 359(5): 518 - 520.
[Full Text] [PDF]


Home page
CirculationHome page
L. Gomez, M. Paillard, H. Thibault, G. Derumeaux, and M. Ovize
Inhibition of GSK3{beta} by Postconditioning Is Required to Prevent Opening of the Mitochondrial Permeability Transition Pore During Reperfusion
Circulation, May 27, 2008; 117(21): 2761 - 2768.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
S. J. Clarke, I. Khaliulin, M. Das, J. E. Parker, K. J. Heesom, and A. P. Halestrap
Inhibition of Mitochondrial Permeability Transition Pore Opening by Ischemic Preconditioning Is Probably Mediated by Reduction of Oxidative Stress Rather Than Mitochondrial Protein Phosphorylation
Circ. Res., May 9, 2008; 102(9): 1082 - 1090.
[Abstract] [Full Text] [PDF]


Home page
Physiol. Rev.Home page
E. Murphy and C. Steenbergen
Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury
Physiol Rev, April 1, 2008; 88(2): 581 - 609.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
M. Ruiz-Meana, P. Pina, D. Garcia-Dorado, A. Rodriguez-Sinovas, I. Barba, E. Miro-Casas, M. Mirabet, and J. Soler-Soler
Glycine protects cardiomyocytes against lethal reoxygenation injury by inhibiting mitochondrial permeability transition
J. Physiol., August 1, 2004; 558(3): 873 - 882.
[Abstract] [Full Text] [PDF]



Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.