| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1Hatter Institute and Center for Cardiology, University College London Hospitals and Medical School, and 2Mitochondrial Biology Group, Department of Physiology, University College London, London, United Kingdom
Submitted 30 November 2004 ; accepted in final form 1 March 2005
After an episode of myocardial ischemia, opening of the mitochondrial permeability transition pore (mPTP), at the onset of reperfusion, is a critical determinant of myocyte death. We investigated the role of the mPTP as a target for cardioprotection in the human heart. We subjected human atrial tissue, harvested from patients undergoing cardiac surgery, to a period of lethal hypoxia and investigated the effect of suppressing mPTP opening at the onset of reoxygenation. We found that suppressing mPTP opening at the onset of reoxygenation with known mPTP inhibitors cyclosporin A (CsA, 0.2 µmol/l) and sanglifehrin A (SfA, 1.0 µmol/l) 1) improved recovery of baseline contractile function from 29.4 ± 2.0% under control conditions to 48.7 ± 2.2% with CsA and 46.1 ± 2.3% with SfA (P < 0.01) and 2) improved cell survival from 62.8 ± 5.3% under hypoxic control conditions to 91.4 ± 4.1% with CsA and 87.2 ± 6.2% with SfA (P < 0.001). Furthermore, with a cell model in which oxidative stress was used to induce mPTP opening in human atrial myocytes, we demonstrated directly that CsA and SfA mediated their cardioprotective effects by inhibiting mPTP opening, as evidenced by an extension in the time required to induce mPTP opening from 116 ± 8 s under control conditions to 189 ± 10 s with CsA and 183 ± 12 s with SfA (P < 0.01). We report that suppressing mPTP opening at the onset of reoxygenation protects human myocardium against lethal hypoxia-reoxygenation injury. This suggests that, in the human heart, the mPTP is a viable target for cardioprotection.
hypoxia-reoxygenation; human cardiac muscle
This article has been cited by other articles:
|
|
 |
|
  C. Fu, C. Wu, T. Liu, T. Ago, P. Zhai, J. Sadoshima, and H. Li Elucidation of Thioredoxin Target Protein Networks in Mouse Mol. Cell. Proteomics, July 1, 2009; 8(7): 1674 - 1687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Puente-Maestu, J. Perez-Parra, R. Godoy, N. Moreno, A. Tejedor, A. Torres, A. Lazaro, A. Ferreira, and A. Agusti Abnormal Transition Pore Kinetics and Cytochrome C Release in Muscle Mitochondria of Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Cell Mol. Biol., June 1, 2009; 40(6): 746 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. N. Dedkova and L. A. Blatter Characteristics and function of cardiac mitochondrial nitric oxide synthase J. Physiol., February 15, 2009; 587(4): 851 - 872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. G. Katare, M. Ando, Y. Kakinuma, M. Arikawa, T. Handa, F. Yamasaki, and T. Sato Vagal nerve stimulation prevents reperfusion injury through inhibition of opening of mitochondrial permeability transition pore independent of the bradycardiac effect. J. Thorac. Cardiovasc. Surg., January 1, 2009; 137(1): 223 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. G. Leshnower, S. Kanemoto, M. Matsubara, H. Sakamoto, R. Hinmon, J. H. Gorman III, and R. C. Gorman Cyclosporine Preserves Mitochondrial Morphology After Myocardial Ischemia/Reperfusion Independent of Calcineurin Inhibition Ann. Thorac. Surg., October 1, 2008; 86(4): 1286 - 1292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 F. N. Obame, C. Plin-Mercier, R. Assaly, R. Zini, J. L. Dubois-Rande, A. Berdeaux, and D. Morin Cardioprotective Effect of Morphine and a Blocker of Glycogen Synthase Kinase 3{beta}, SB216763 [3-(2,4-Dichlorophenyl)-4(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione], via Inhibition of the Mitochondrial Permeability Transition Pore J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 252 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 M. Ruiz-Meana, A. Rodriguez-Sinovas, A. Cabestrero, K. Boengler, G. Heusch, and D. Garcia-Dorado Mitochondrial connexin43 as a new player in the pathophysiology of myocardial ischaemia-reperfusion injury Cardiovasc Res, January 15, 2008; 77(2): 325 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Jahangir, S. Sagar, and A. Terzic Aging and cardioprotection J Appl Physiol, December 1, 2007; 103(6): 2120 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Yellon and D. J. Hausenloy Myocardial Reperfusion Injury N. Engl. J. Med., September 13, 2007; 357(11): 1121 - 1135. [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Kang, W. S. Park, N. Kim, J. B. Youm, M. Warda, J.-H. Ko, E. A Ko, and J. Han Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H307 - H313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Kroemer, L. Galluzzi, and C. Brenner Mitochondrial Membrane Permeabilization in Cell Death Physiol Rev, January 1, 2007; 87(1): 99 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-S. Park, H. Zhao, Y. Jang, R. A. Mueller, and Z. Xu N6-(3-Iodobenzyl)-adenosine-5'-N-methylcarboxamide Confers Cardioprotection at Reperfusion by Inhibiting Mitochondrial Permeability Transition Pore Opening via Glycogen Synthase Kinase 3beta J. Pharmacol. Exp. Ther., July 1, 2006; 318(1): 124 - 131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Bovill Intravenous Anesthesia for the Patient with Left Ventricular Dysfunction Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2006; 10(1): 43 - 48. [Abstract] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
