Published online before print July 26, 2004, doi: 10.1161/01.CIR.0000136997.53612.6C
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2004;110:534-539.)
© 2004 American Heart Association, Inc.
Original Articles |
Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery
From the Cardiovascular Branch (C.J.M., A.P.J., M.N.S.) and Laboratory of Animal Medicine and Surgery (R.C., R.F.H.), NHLBI, National Institutes of Health, Bethesda, Md; and the Hatter Institute for Cardiology Research, University of Cape Town Medical School, Cape Town, South Africa (J.O.M.).
Correspondence to Michael N. Sack, MD, PhD, NHLBI/NIH, Building 10, Room 7B/15, 10 Center Dr, Bethesda, MD 20892-1650. E-mail sackm{at}nih.gov
Received August 22, 2003; de novo received February 25, 2004; revision received March 23, 2004; accepted March 26, 2004.
Background— Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program.
Methods and Results— Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (P<0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (
22% versus control, P<0.001). After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191±12% improvement in ADP-sensitive respiration (P=0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator–activated receptor gamma coactivator 1
, were significantly induced in preconditioned myocardium.
Conclusions— Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.
Key Words: ischemia • preconditioning • mitochondria • metabolism
This article has been cited by other articles:
 |
|
 |
|
  Z. Lu, I. Scott, B. R. Webster, and M. N. Sack The Emerging Characterization of Lysine Residue Deacetylation on the Modulation of Mitochondrial Function and Cardiovascular Biology Circ. Res., October 23, 2009; 105(9): 830 - 841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, L. Ebermann, A. Sterner-Kock, S. Wika, H.-P. Schultheiss, A. Dörner, and T. Walther Myocardial overexpression of adenine nucleotide translocase 1 ameliorates diabetic cardiomyopathy in mice Exp Physiol, February 1, 2009; 94(2): 220 - 227. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Ventura-Clapier, A. Garnier, and V. Veksler Transcriptional control of mitochondrial biogenesis: the central role of PGC-1{alpha} Cardiovasc Res, July 15, 2008; 79(2): 208 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Yu, T. Nguyen, M. Ogbi, R. W. Caldwell, and J. A. Johnson Differential loss of cytochrome-c oxidase subunits in ischemia-reperfusion injury: exacerbation of COI subunit loss by PKC-{varepsilon} inhibition Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2637 - H2645. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shiva, M. N. Sack, J. J. Greer, M. Duranski, L. A. Ringwood, L. Burwell, X. Wang, P. H. MacArthur, A. Shoja, N. Raghavachari, et al. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer J. Exp. Med., September 3, 2007; 204(9): 2089 - 2102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Walther, C. Tschope, A. Sterner-Kock, D. Westermann, S. Heringer-Walther, A. Riad, A. Nikolic, Y. Wang, L. Ebermann, W.-E. Siems, et al. Accelerated Mitochondrial Adenosine Diphosphate/Adenosine Triphosphate Transport Improves Hypertension-Induced Heart Disease Circulation, January 23, 2007; 115(3): 333 - 344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Sack Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance Cardiovasc Res, November 1, 2006; 72(2): 210 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Das and N. Maulik Cardiac genomic response following preconditioning stimulus Cardiovasc Res, May 1, 2006; 70(2): 254 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Moses, P. D. Addison, P. C. Neligan, H. Ashrafpour, N. Huang, S. E. McAllister, J. E. Lipa, C. R. Forrest, and C. Y. Pang Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: efficacy and mechanism Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1609 - R1617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. McLeod, A. Aziz, R. F. Hoyt Jr., J. P. McCoy Jr., and M. N. Sack Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia J. Biol. Chem., September 30, 2005; 280(39): 33470 - 33476. [Abstract] [Full Text] [PDF]
|
|