Skip Navigation

Cardiovascular Research 2006 69(1):178-185; doi:10.1016/j.cardiores.2005.07.014
This Article
Right arrow Abstract 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 Bopassa, J.-C.
Right arrow Articles by Ovize, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bopassa, J.-C.
Right arrow Articles by Ovize, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2005, European Society of Cardiology

PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning

Jean-Chrisostome Bopassaa, René Ferreraa, Odile Gateau-Roescha,b, Elisabeth Couture-Lepetita and Michel Ovizea,b,*

aINSERM E0226, Université Claude Bernard Lyon I, Laboratoire de Physiologie Lyon-Nord 8, avenue Rockefeller, 69373 LYON Cedex 08, France
bHospices Civils de Lyon, France

* Corresponding author. INSERM E0226, Université Claude Bernard Lyon I, Laboratoire de Physiologie Lyon-Nord 8, avenue Rockefeller, 69373 LYON Cedex 08, France Tel.: +33 4 78 77 70 74; fax: +33 4 78 77 71 75. Email address: ovize{at}sante.univ-lyon1.fr

Received 16 February 2005; revised 13 July 2005; accepted 15 July 2005


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: We investigated whether phosphatidylinositol 3-kinase (PI3K) might regulate mitochondrial permeability transition pore (mPTP) opening in hearts reperfused with either low pressure or postconditioning.

Methods: Male Wistar rat hearts (n=72) were perfused according to the Langendorff technique, exposed to 30 min of ischemia, and assigned to one of the following groups: (1) reperfusion with normal pressure (NP; 100 cm H2O), (2) reperfusion with low pressure (LP; 70 cm H2O), or reperfusion with postconditioning, i.e. 3 episodes of 30 s reperfusion followed by 30 s of ischemia (PostC). Hearts received either the PI3K inhibitors wortmannin or LY294002, or vehicle at the onset of the 60 min reperfusion. Postischemic functional recovery was assessed by rate–pressure product (RPP), and irreversible injury by lactate dehydrogenase (LDH), creatine kinase (CK) and troponin I (TnI) release. Mitochondria were isolated from the reperfused myocardium, and Ca2+-induced mPTP opening was measured using a potentiometric method.

Results: Functional recovery was significantly improved in LP and PostC hearts with RPP averaging 13,880 ± 810 (LP) and 17,130 ± 900 mm Hg x beats/min (PostC) versus 6450 ± 500 mm Hg x beats/min in NP hearts (p<0.01). LDH release averaged 230 ± 30 and 145 ± 15 IU/h/g of myocardial tissue in LP and PostC versus 340 ± 10 IU/h/g in NP (p<0.05). Wortmannin and LY294002 prevented both RPP improvement and decrease in LDH, CK, and TnI release in LP and PostC groups. The Ca2+ load required to induce mPTP opening averaged 58 ± 3 and 52 ± 1 nmol/mg mitochondrial proteins in LP and PostC groups, respectively, versus 35 ± 4 nmol/mg in the NP group (p<0.01). Wortmannin and LY294002 prevented the beneficial effect in both the LP and PostC groups.

Conclusion: These results suggest that PI3K regulates the opening of the mitochondrial permeability transition pore in rat hearts reperfused with low pressure or postconditioning.

KEYWORDS Ischemia; Reperfusion; Postconditioning


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
It is widely recognized that timely reperfusion after prolonged ischemia is a prerequisite to attenuate myocardial damage following the ischemic insult [1,2]. On the other hand, abrupt restoration of blood flow into the ischemic myocardium favors ventricular arrhythmias, myocardial stunning and no-reflow phenomenon [3–6]. Zhao et al. first demonstrated that brief episodes of ischemia–reperfusion performed just at the onset of reperfusion reduce infarct size to a comparable extent than ischemic preconditioning: they named this phenomenon "postconditioning" [7]. Recently, Tsang et al. reported that postconditioning involves the activation of phosphatidylinositol 3-kinase (PI3K)–Akt pathway in the isolated rat model [8]. While opening of the mitochondrial permeability transition pore (mPTP) upon reperfusion has been implicated in lethal myocardial reperfusion injury [9–14], our laboratory recently demonstrated that postconditioning inhibits mitochondrial permeability transition in the rabbit heart [15]. However, a direct link between PI3K and the mitochondrial permeability transition pore remains to be established in the postconditioned heart.

Previous studies demonstrated that "controlled reperfusion", with reduction of oxygen tension or coronary pressure, can protect the ischemic heart and attenuate postischemic contractile dysfunction [16–18]. The mechanism of this protection is incompletely understood and has been attributed to a reduced production of reactive oxygen species and/or limited accumulation of Na+ and Ca2+ [19]. The analogy between experimental designs led to question whether postconditioning might be an active form of controlled reperfusion, and to consider that low-pressure, low-flow or low-oxygen reperfusion would be a passive phenomenon [8,20].

The objective of the present study was therefore to address whether low-pressure reperfusion, as compared to postconditioning, might protect the rat heart via (1) activation of PI3K, and (2) inhibition of the mPTP, and (3) whether the two events might be linked.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Surgical preparation
The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publication No. 85-23, revised 1996).

Male Wistar rats, weighting 350 to 450 g, were anesthetized with pentobarbital (50 mg/kg), and heparin (200 UI/kg) was injected into the femoral vein. Hearts were removed and immediately arrested in ice-cold Krebs solution. The aorta was rapidly cannulated and perfused for 10 min in the Langendorff mode using Krebs–Henseleit bicarbonate buffer (containing in mmol/L: glucose 11.0, NaCl 118.5, KCl 4.75, MgSO4 1.19, KH2PO4 1.18, NaHCO3 25.0, CaCl2 1.4) at pH 7.4. The buffer was bubbled with 95% O2/5% CO2 at 37 °C and perfusion was performed under a hydrostatic pressure of 100 cm H2O. The left ventricle was paced at a constant rate of 300 beats/min.

2.2 Experimental design
Global normothermic ischemia was induced by clamping the aorta, as previously described [21]. The temperature was maintained by immersing the heart in the perfusion medium at 37 °C. Two different protocols were performed. Protocol I aimed at evaluating functional recovery and tissue injury following 30 min of global ischemia and 60 min of reperfusion. Protocol II was used to assess Ca2+-induced mitochondrial permeability transition.

2.3 Protocol I
One group of hearts underwent no intervention for the whole duration of the experiment (sham, n=6). All other hearts underwent 30 min of global ischemia followed by 60 min of reperfusion. Animals were randomly assigned into one of the nine following groups (n=6/group):

  • NP group (normal pressure): myocardium was reperfused at normal pressure (i.e. 100 cm H2O) following the ischemic insult
  • LP group (low pressure): myocardium was reperfused at a pressure of 70 cm H2O
  • PostC group (postconditioning): after 1 min of reflow, 3 episodes of 30 s of global ischemia, each separated by 30 s of reperfusion, were performed. Then, reperfusion at normal pressure was maintained for the remaining of the experiment.
  • NP-WT, LP-WT and PostC-WT groups (n=6/group): in these NP, LP and PostC hearts, wortmannin (100 nmol/L) was administered at the onset of reperfusion. This dose was chosen because it has been reported to block postconditioning in the isolated rat heart.
  • NP-LY, LP-LY and PostC-LY groups (n=6/group): in these NP, LP and PostC hearts, the selective PI3K inhibitor LY294002 (15 µmol/L) was administered at the onset of reperfusion.

These two levels of perfusion pressure were obtained by adjusting the perfusion column to the adequate height. It can be noted that 100 cm H2O is considered as a normal perfusion pressure for a rat heart under physiologic conditions [21]. We used 70 cm H2O as "low pressure" because we previously demonstrated that it can protect the heart [21].

2.4 Protocol II
All hearts underwent 30 min of global ischemia followed by 10 min of reperfusion. Animals were randomly assigned into one of the six previously defined groups (n=6/group). At the end of the 10-min reperfusion, hearts were excised for assessment of Ca2+-induced mPTP opening.

2.5 Analysis
2.5.1 Functional recovery
The left ventricular systolic pressure (LVSP) and the left ventricular end-diastolic pressure (LVEDP) were measured using a latex balloon introduced in the left ventricle and expanded to exert a physiologic end-diastolic pressure of 5 mm Hg. LV developed pressure (LVDP) was calculated as : LVDP=LVSP–LVEDP. The rate–pressure product (RPP=(LVSP–LVEDP) x HR), the maximum rate of rise of the LV pressure (dP/dt max) and the maximum isovolumetric rate of relaxation (–dP/dt min) were calculated. Coronary Flow (CF) was measured by timed collections of the coronary effluent.

2.5.2 Myocardial necrosis
Myocardial necrosis was evaluated by measurement of the release of creatine kinase (CK), lactate dehydrogenase (LDH) and troponin I (TnI) in the coronary effluent during the 60 min reperfusion period (Beckman Coulter® kit, Galway, Ireland).

2.5.3 Ca2+-induced mitochondrial permeability transition
2.5.3.1 Preparation of isolated mitochondria
Preparation of mitochondria was adapted from a previously described procedure [22]. All operations were carried out in the cold. Myocardial sections (approximately 1 g) were placed in isolation buffer A containing 70 mM sucrose, 210 mM mannitol, 1 mM EDTA in 50 mM Tris/HCl pH 7.4. The tissue was finely minced with scissors and then homogenized in the same buffer (1 ml buffer/g tissue), using successively a Kontes tissue grinder and a Potter Elvejem. The homogenate was centrifuged at "1300 g" for 3 min. The supernatant was poured through cheesecloth and centrifuged at "10,000 x g" for 10 min. The mitochondrial supernatant was frozen (–80 °C) for subsequent measurements (Western blotting for phospho-Akt). The mitochondrial pellet was resuspended in isolation buffer B containing 70 mM sucrose, 210 mM mannitol, 0.1 mM EDTA in 50 mM Tris/HCl pH 7.4. After aliquots were removed for protein measurements, the mitochondria (by aliquots of 5 mg proteins) were washed in isolation buffer B, centrifuged at "6800 x g" for 10 min and stored as pellets on ice prior to mPTP opening experiments. Protein content was routinely assayed according to Gornall's procedure using bovine serum albumin as a standard [23]. All chemicals were purchased from Sigma Aldrich (France).

2.5.4 Ca2+-induced MPT pore opening
The mPTP opening was assessed following in vitro Ca2+ overload. Isolated mitochondria (5 mg proteins) were suspended in 100 µl buffer B, and added in 900 µl of buffer C (150 mM sucrose, 50 mM KCl, 2 mM KH2PO4, 5 mM succinic acid to 20 mM Tris/HCl pH 7.4) within a Teflon chamber equipped with a Ca2+-specific microelectrode, in conjunction with reference electrode (Radiometer Analytical (Lyon, France) [12]. Modifications of the medium (i.e. extra-mitochondrial) Ca2+ concentration were continuously recorded using a custom made Synchronie® software. Mitochondria were gently stirred for a 1.5 min. At the end of the pre-incubation period, 20 µM CaCl2 administrations were repeated every 60 s. As depicted in Fig. 1, each 20 µM CaCl2 administration induces an abrupt rise in extramitochondrial Ca2+concentration. Ca2+ is then rapidly taken up by the mitochondria resulting in a return of extramitochondrial Ca2+ concentration to near baseline level. Following sufficient Ca2+ loading, extra-mitochondrial Ca2+ concentration abruptly increases indicating a massive release of Ca2+ by mitochondria due to MPT pore opening (Fig. 1). The amount of Ca2+ required to trigger this massive Ca2+ release is used here as an indicator of the susceptibility of the mPTP pore to Ca2+ overload.


Figure 1
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Ca2+-induced mPTP opening. Typical recording of mPTP opening in isolated mitochondria obtained from one NP (normal pressure), one LP (low pressure) and one PostC (postconditioned) hearts. In the NP mitochondria, a Ca2+ overload of 160 nmol (8 pulses of 20 µM) was required to induce mPTP opening. In LP and PostC mitochondria, a significantly higher Ca2+ overload (300 and 260 nmol, respectively) were required to induce MPT pore opening. Vertical arrows indicate the first administration of 20 µM of Ca2+ into the NP or LP mitochondria suspension. Each spike of Ca2+concentration results from a repeated administration of 20 µM of Ca2+.

 
2.6 Western blotting for phospho-Akt
The protein concentration of mitochondrial supernatant (obtained during isolated mitochondria preparation) was assayed using a BCA protein assay kit standardized to BSA, according to the manufacturer's protocol. For electrophoresis, 50 µg of protein were loaded on a 10% Tris–HCl SDS polyacrylamide gel. Protein was electrotransferred to a nitrocellulose membrane and then blocked with 5% nonfat dry milk in 20 mM of TBS with 0.1% Tween. After blocking, the membrane was incubated overnight at 4 °C with phosphorylated Akt (p-Akt)-specific primary antibodies using a dilution of 1/1000 by incubation with the corresponding secondary antibody of 1/2000 at room temperature. After washing three times, bands were detected using ECL-plus reagents (Amersham Pharmacia Biotech). The membranes were then stripped with Immuno Pure IgG Elution Buffer (Pierce), and reblotted with specific antibodies for total Akt measurements.

2.7 Statistics
Statistical comparisons were performed using the analysis of variance and Fischer PLSD test. All results are expressed as mean ± standard error of the mean (SEM). A p value less than 0.05 was considered as indicative of a statistically significant difference.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Protocol I : tissue damage and postischemic functional recovery
3.1.1 Irreversible myocardial damage
At 60 min of reperfusion, LDH, CK and TnI release averaged 340 ± 10 IU/h/g tissue, 470 ± 70 IU/h/g tissue and 13 ± 2 IU/h/g tissue in NP hearts, respectively (Table 1). LDH, CK and TnI release was significantly reduced in LP and PostC groups (p<0.05 versus NP, see Table 1). In NP hearts, wortmannin and LY294002 did not alter LDH, CK and TnI release. Wortmannin and LY294002 both prevented the decrease in LDH, CK and TnI release in LP and PostC hearts (p<0.05 versus LP and PostC, not significantly different from NP).


View this table:
[in this window]
[in a new window]

  		Table 1 Irreversible myocardial damage

 
3.2 Postischemic functional recovery
In the sham group, RPP average 31,200 ± 3100 mm Hg x beats/min at baseline, and did not significantly vary throughout the time of the experiment. In the NP group, baseline RPP averaged 30,060 ± 2700 mm Hg x beats/min. During the reperfusion period, recovery was poor with RPP and LVDP averaging 6445 ± 500 mm Hg x beats/min and 21 ± 1 mm Hg, respectively, at 60 min of reperfusion (p<0.001 versus baseline and sham) (Table 2). In the LP and PostC groups, baseline RPP and LVDP was comparable to that of the NP group. During the reperfusion period, functional recovery was significant improved in both LP and PostC. Both wortmannin and LY294002 significantly attenuated the increase in RPP and LVDP observed in LP and PostC groups (Table 2). At 60 min of reperfusion, coronary flow was not significantly different among NP and PostC groups, averaging 9.4 ± 0.4 and 10.1 ± 0.5 ml/min/g, respectively. As expected, coronary flow was significantly reduced in the LP groups, averaging 7.2 ± 0.6 ml/min/g (p<0.05 versus control). Neither wortmannin nor LY294002 significantly modified coronary flow in either group. In the NP group, LV dP/dt max and LV dP/dt min were significantly decreased, averaging 370 ± 80 and 330 ± 50 mm Hg/s at 60 min of reperfusion, respectively (p<0.01 versus sham). LP and PostC groups exhibited increased LV dP/dt max (1650 ± 130 and 1210 ± 90 mm Hg/s, respectively) and increased LV dP/dt min (1050 ± 60 and 830 ± 70 mm Hg/s, respectively). Wortmannin and LY294002 fully prevented this improvement with LV dP/dt max and LV dP/dt min no longer different from those in NP group.


View this table:
[in this window]
[in a new window]

  		Table 2 Functional recovery at 60 min of reperfusion

 
3.3 Protocol II
3.3.1 Ca2+-induced mPTP opening
In the NP group, the amount of Ca2+ required to open the mPTP averaged 35 ± 4 nmol/mg mitochondrial proteins (Fig. 2). This Ca2+ load was significantly increased in both the LP and PostC groups, averaging 58 ± 3 and 52 ± 1 nmol/mg mitochondrial proteins, respectively (p<0.01 versus NP). Wortmannin and LY294002 had no significant effect in NP hearts. Wortmannin and LY294002 prevented the enhanced resistance of the mPTP to Ca2+-induced opening in LP and PostC hearts, since the Ca2+ load required to open the mPTP averaged 38 ± 2 and 35 ± 5 nmol/mg mitochondrial proteins for wortmannin and 38 ± 4 and 38 ± 4 nmol/mg mitochondrial proteins for LY294002, respectively, in these two groups, i.e. a value comparable to that of NP hearts (p<0.05 versus LP and PostC, non significant versus NP) (Fig. 2).


Figure 2
View larger version (35K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Ca2+-induced mitochondrial permeability transition pore opening. Ca2+ load required to induce mPTP opening in hearts reperfused for 10 min at low (LP, 70 cm H2O), normal pressure (NP, 100 cm H2O) or with postconditioning (PostC), with or without administration of wortmannin (Wt) and LY294002. *p<0.05 versus NP, {dagger}p<0.05 versus untreated matched group.

 
3.4 Western blot for phospho-Akt
As depicted in Fig. 3, at 10 min of reperfusion, phospho-Akt was significantly increased in both LP and PostC hearts when compared to controls. Wortmannin and LY294002 significantly attenuated this increased phosphorylation in the LP as well as in the PostC group.


Figure 3
View larger version (52K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Western Blot for phospho-Akt. Typical example of phospho-Akt measured at 10 min of reperfusion following the 30 min ischemia. Bar graph represents averaged phospho-Akt expressed as percentage of total Akt. Increased phosphorylation in LP and PostC hearts was blocked by wortmannin and LY294002.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In the present study, we report that the comparable protection afforded by low-pressure reperfusion and postconditioning involves activation of the PI3kinase–mPTP pathway.

4.1 Low-pressure reperfusion activates PI3K and mimics postconditioning
Postconditioning has been shown to protect the ischemic heart in various experimental models [7,24,25]. In agreement with a recent report, we demonstrated in the present study that postconditioning attenuates lethal reperfusion injury and improves postischemic functional recovery in the isolated rat heart model [8]. This protection likely involves activation of PI3K, since both attenuation of LDH, CK and Troponin I release and improvement in rate–pressure product were abolished by wortmannin and LY294002 given at the time of reflow.

The peculiar protocol of repeated brief episodes of ischemia–reperfusion at the time of reflow leads to question whether postconditioning might simply be a form of "controlled reperfusion" [8,20]. Modulation of the conditions of reperfusion has long been proven to be able to protect the ischemic heart [18,26,27]. Previous studies demonstrated that controlling coronary reperfusion pressure or flow can improve functional recovery after brief or prolonged ischemic insult [16,17,21,27–29]. We further demonstrated here that the protection afforded by low-pressure reperfusion closely resembles that of postconditioning in the isolated rat heart, since the amplitude of the protective effects is very similar. Other interventions including low-oxygen tension, delayed correction of acidosis, reduced Ca2+ overload at the time of reflow have been shown to prevent hypercontracture and attenuate lethal cardiomyocyte injury [19,28].

Despite the apparent similarity between postconditioning and Controlled Reperfusion, it has been questioned that the latter might be a passive phenomenon, as opposed to the active protection that would characterize the former [8]. In the present study, we demonstrated that wortmannin and LY294002 block the beneficial effect of low-pressure reperfusion on both infarct size and postischemic functional recovery. Phosphorylation of Akt was enhanced in low-pressure as well as in postconditioned hearts, and it was prevented in both groups by the two inhibitors of PI3K. This strongly suggests that low-pressure reperfusion is indeed an active protection that shares PI3K activation with postconditioning.

4.2 Low-pressure reperfusion inhibits mPTP opening downstream PI3K
We sought to determine what downstream effector of PI3K might be involved in low-pressure reperfusion-induced protection. PI3K, known as a key player of the so-called "survival pathway", has been clearly involved in ischemic preconditioning protection [30,31]. Several pharmacological agents known to activate the PI3K–Akt pathway, including insulin and bradykinin, limit infarct size when given at the time of reflow following a prolonged ischemia [32–34]. PI3K activation induces phosphorylation of the seronine–threonine kinase Akt that subsequently inhibits the formation of several proapoptotic proteins of the Bcl-2 family, stimulates endothelial nitric oxide synthase (eNOS), PKC and mTOR/p70s6K, and inhibits downstream glycogen synthase kinase-3β [31,35–37]. Several of these target proteins have been shown elsewhere to modify either mitochondrial K+ATP channels or mitochondrial permeability transition [38–40]. We recently demonstrated that postconditioning, as well as preconditioning, inhibits mPTP opening in the in vivo rabbit heart [15]. However, whether PI3K regulates mPTP opening in the postconditioned or during "controlled reperfusion" is currently unknown. We demonstrated here that mitochondria isolated from hearts reperfused with low-pressure as well as from postconditioned hearts display a delayed opening of the mitochondrial transition pore following in vitro Ca2+overload. Previous report from our laboratory indicates that this pattern is very similar to that seen in either in vivo rabbit hearts or in isolated rat hearts that had been pretreated with the mPTP inhibitor cyclosporin A [15,41]. This finding is consistent with recent reports, including from our group, indicating that inhibition of mitochondrial permeability transition is involved in protection afforded by ischemic preconditioning [12–14,35]. In addition, administration of wortmannin and LY294002 at the time of reflow fully prevented mPTP opening inhibition observed in low-pressure and postconditioned hearts. This demonstrates that the mPTP is inhibited as a result of the activation of the PI3K pathway.

Clarifying the precise link between PI3K activation and inhibition of mitochondrial permeability transition by low-pressure reperfusion or postconditioning will require further investigations. Among several possibilities, determination of the role of the activation of the mK+ATP channel, attenuation of ROS production by the respiratory chain, limitation of the accumulation of Ca2+, control of acidosis within the mitochondrial matrix, or direct regulation of the mPTP by Bcl-2 proteins or constitutive proteins of the mega-channel will probably be worthwhile.

In conclusion, the present results suggest that both postconditioning and low-pressure reperfusion protect the isolated rat heart via activation of the PI3K–mPTP pathway. Similarities between these two examples of cardioprotection would suggest that they possibly represent two specific forms of a larger group of interventions performed in a narrow time window at the onset of reflow and aimed at limiting reperfusion injury. Potential application of these two phenomena to human care enlightens the need for further research focused on the mechanisms of lethal reperfusion injury within the first minutes of reflow. Although low-pressure reperfusion or repetition or brief episodes of ischemia–reperfusion may be performed in some clinical situations, major issue is the development of drugs able to directly or indirectly inhibit mitochondrial permeability transition, to be used in patients with acute myocardial infarction undergoing coronary angioplasty or thrombolysis.


   Acknowledgements
 
The authors are grateful to Perrine Galia for her excellent technical assistance.


   Notes
 
Time for primary review 13 days


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Jennings R.B., Reimer K.A. Factors involved in salvaging ischemic myocardium: effect of reperfusion of arterial blood. Circulation (1983) 68(Suppl. I):I25–I36.[Medline]
  2. Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival. Should the paradigm be expanded? Circulation (1989) 2:441–444.
  3. Opie L.H. Reperfusion injury and its pharmacological modification. Circulation (1989) 80:1049–1062.[Abstract/Free Full Text]
  4. Heyndrickx G.R., Millard R.W., McRitchie R.J., Maroko P.R., Vatner S.F. Regional myocardial functionnal and electrophysiological alterations after brief coronary artery occlusion in conscious dogs. J Clin Invest (1975) 56:978–985.[Web of Science][Medline]
  5. Braunwald E., Kloner R.A. Myocardial reperfusion: a double-edged sword? J Clin Invest (1985) 76:1713–1719.[Web of Science][Medline]
  6. Kloner R.A., Ganote C.E., Jennings R.B. The "no-reflow" phenomenon after temporary coronary occlusion in the dog. J Clin Invest (1974) 54:1496–1508.[Web of Science][Medline]
  7. Zhao Z.Q., Corvera J.S., Halkos M.E., Kerendi F., Wang N.P., Guyton R.A., et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol (2003) 285:H579–H588.[Abstract/Free Full Text]
  8. Tsang A., Hausenloy D.J., Mocanu M.M., Yellon D.M. Postconditioning: a form of modified reperfusion protects the myocardium by activating the phosphatidylinositol 3-kinase–Akt pathway. Circ Res (2004) 95:230–232.[Abstract/Free Full Text]
  9. Nazareth W., Yafei N., Crompton M. Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol (1991) 23:1351–1354.[CrossRef][Web of Science][Medline]
  10. Duchen M.R., McGuiness O., Brown L.A., Crompton M. On the involvement of a cyclosporin A sensitive mitochondrial pore in myocardial reperfusion injury. Cardiovasc Res (1993) 27:1790–1794.[Free Full Text]
  11. Bernardi P., Petronelli V. The permeability transition pore as a mitochondrial calcium release channel: a critical appraisal. J Bioenerg Biomembr (1996) 28:129–136.
  12. Argaud L., Gateau-Roesch O., Chalabreysse L., Gomez L., Loufouat J., Thivolet-Bejui F., et al. Preconditioning delays Ca2+-induced mitochondrial permeability transition. Cardiovasc Res (2004) 61:115–122.[Abstract/Free Full Text]
  13. Hausenloy D.J., Maddock H.L., Baxter G.F., Yellon D.M. Inhibiting mitochondrial permeability transition pore opening : a new paradigm for myocardial preconditioning? Cardiovas Res (2002) 55:534–543.[Abstract/Free Full Text]
  14. Javadov S.A., Clarke S., Das M., Griffiths E.J., Lim K.H., Halestrap A.P. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol (2003) 549:513–524.[Abstract/Free Full Text]
  15. Argaud L., Gateau-Roesch O., Raisky O., Loufouat J., Robert D., Ovize M. Postconditioning inhibits mitochondrial permeability transition. Circulation (2005) 111(2):194–197.[Abstract/Free Full Text]
  16. Okamoto F., Allen B.S., Buckberg G.D., Bugyi H. Studies of controlled reperfusion after ischemia. XIV. Reperfusion conditions: importance of ensuring gentle versus sudden reperfusion during relief of coronary occlusion. J Thorac Cardiovasc Surg (1986) 92:613–620.[Abstract]
  17. Takeo S., Liu J.X., Tanonaka K., Nasa Y., Yabe K., Tanahashi H., et al. Reperfusion at reduced flow rates enhances postischemic contractile recovery of perfused heart. Am J Physiol Heart Circ Physiol (1995) 268:H2384–H2395.[Abstract/Free Full Text]
  18. Rosenkranz E.R., Buckberg G.D. Myocardial protection during surgical coronary reperfusion. J Am Coll Cardiol (1983) 1(5):1235–1246.[Abstract]
  19. Piper H.M., Meuter K., Schafer C. Cellular mechanisms of ischemia–reperfusion injury. Ann Thorac Surg (2003) 75:S644–S648.[Abstract/Free Full Text]
  20. Heusch G. Postconditioning: old wine in a new bottle? J Am Coll Cardiol (2004) 44:1111–1112.[Free Full Text]
  21. Bopassa J.C., Michel P., Gateau-Roesch O., Ovize M., Ferrera R. Low pressure reperfusion alters mitochondrial permeability transition. Am J Physiol Heart Circ Physiol (2005) 288:2750–2755.[CrossRef]
  22. Gateau-Roesch O., Pavlov E., Lazareva A.V., Limarenko E.A., Levrat C., Saris N.E., et al. Calcium-binding properties of the mitochondrial channel-forming hydrophobic component. J Bioenerg Biomembr (2000) 32:105–110.[CrossRef][Web of Science][Medline]
  23. Gornall A.G., Bardawill C.J., David H.M. Determination of serum proteins by means of biuret reaction. J Biol Chem (1973) 248:751–766.
  24. Kin H., Zhao Z.Q., Sun H.Y., Wang N.P., Corvera J.S., Halkos M.E., et al. Postconditioning attenuates myocardial ischemia–reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res (2004) 62:74–85.[Abstract/Free Full Text]
  25. Yang X.M., Proctor J.B., Cui L., Krieg T., Downey J.M., Cohen M.V. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol (2004) 44(5):1103–1110.[Abstract/Free Full Text]
  26. Buckberg G.D. Studies of controlled reperfusion after ischemia. I. When is cardiac muscle damaged irreversibly? J Thorac Cardiovasc Surg (1986) 92:483–487.[Web of Science][Medline]
  27. Beyersdorf F., Sarai K., Maul F.D., Wendt T., Satter P. Immediate functional benefits after controlled reperfusion during surgical revascularization for acute coronary occlusion. J Thorac Cardiovasc Surg (1991) 102:856–866.[Abstract]
  28. Hori M., Kitakaze M., Sato H., Takashima S., Iwakura K., Inoue M., et al. Staged reperfusion attenuates myocadial stunning in dogs. Role of transient acidosis during early reperfusion. Circulation (1991) 84:2135–2145.[Abstract/Free Full Text]
  29. Klawitter P.F., Murray H.N., Clanton T.L., Palmer B.S., Angelos M.G. Low flow after global ischemia to improve postischemic myocardial function and bioenergetics. Crit Care Med (2002) 30:2542–2547.[CrossRef][Web of Science][Medline]
  30. Hausenloy D.J., Yellon D.M. New directions for protecting the heart against ischaemia–reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res (2004) 61:448–460.[Abstract/Free Full Text]
  31. Tong H., Chen W., Steenbergen C., Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res (2000) 87(4):309–315.[Abstract/Free Full Text]
  32. Jonassen A.K., Sack M.N., Mjos O.D., Yellon D.M. Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res (2001) 89:1191–1198.[Abstract/Free Full Text]
  33. Bell R.M., Yellon D.M. Bradykinin limits infarction when administered as an adjunct to reperfusion in mouse heart: the role of PI3K, Akt and eNOS. J Mol Cell Cardiol (2003) 35:185–193.[CrossRef][Web of Science][Medline]
  34. Yang X.M., Krieg T., Cui L., Downey J.M., Cohen M.V. NECA and bradykinin at reperfusion reduce infarction in rabbit hearts by signaling through PI3K, ERK, and NO. J Mol Cell Cardiol (2004) 36(3):411–421.[CrossRef][Web of Science][Medline]
  35. Juhaszova M., Zorov D.B., Kim S.H., Pepe S., Fu K., Fishbein K.W., et al. Glycogen synthase kinase-3β mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest (2004) 113:1535–1549.[CrossRef][Web of Science][Medline]
  36. Baines C.P., Song C.X., Zheng Y.T., Wang G.W., Zhang J., Wang O.L., et al. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res (2003) 92(8):873–880.[Abstract/Free Full Text]
  37. Uchiyama T., Engelman R.M., Maulik N., Das D.K. Role of Akt signaling in mitochondrial survival pathway triggered by hypoxic preconditioning. Circulation (2004) 109(24):3042–3049.[Abstract/Free Full Text]
  38. Armstrong S.C. Protein kinase activation and myocardial ischemia/reperfusion injury. Cardiovasc Res (2004) 61(3):427–436.[Abstract/Free Full Text]
  39. Chiari P.C., Bienengraeber M.W., Pagel P.S., Krolikowski J.G., Kersten J.R., Warltier D.C. Isoflurane protects against myocardial infarction during early reperfusion by activation of phosphatidylinositol-3-kinase signal transduction: evidence for anesthetic-induced postconditioning in rabbits. Anesthesiology (2005) 102:102–109.[CrossRef][Web of Science][Medline]
  40. Yellon D.M., Downey J.M. Preconditioning the myocardium: from cellular physiology to clinical cardiology. Physiol Rev (2003) 83:1113–1151.[Abstract/Free Full Text]
  41. Argaud L., Gateau-Roesch O., Muntean D., Chalabreysse L., Loufouat J., Robert D., et al. Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol (2005) 38(2):367–374.[CrossRef][Medline]

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
K. Boengler, R. Schulz, and G. Heusch
Loss of cardioprotection with ageing
Cardiovasc Res, July 15, 2009; 83(2): 247 - 261.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
L. Gomez, B. Li, N. Mewton, I. Sanchez, C. Piot, M. Elbaz, and M. Ovize
Inhibition of mitochondrial permeability transition pore opening: translation to patients
Cardiovasc Res, July 15, 2009; 83(2): 226 - 233.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
U. Hofmann, N. Burkard, C. Vogt, A. Thoma, S. Frantz, G. Ertl, O. Ritter, and A. Bonz
Protective effects of sphingosine-1-phosphate receptor agonist treatment after myocardial ischaemia-reperfusion
Cardiovasc Res, July 15, 2009; 83(2): 285 - 293.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
A. Skyschally, P. van Caster, K. Boengler, P. Gres, J. Musiolik, D. Schilawa, R. Schulz, and G. Heusch
Ischemic Postconditioning in Pigs: No Causal Role for RISK Activation
Circ. Res., January 2, 2009; 104(1): 15 - 18.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Kuno, N. V. Solenkova, V. Solodushko, T. Dost, Y. Liu, X.-M. Yang, M. V. Cohen, and J. M. Downey
Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C
Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1288 - H1295.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. E. McAllister, H. Ashrafpour, N. Cahoon, N. Huang, M. A. Moses, P. C. Neligan, C. R. Forrest, J. E. Lipa, and C. Y. Pang
Postconditioning for salvage of ischemic skeletal muscle from reperfusion injury: efficacy and mechanism
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R681 - R689.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
B. Xing, H. Chen, M. Zhang, D. Zhao, R. Jiang, X. Liu, and S. Zhang
Ischemic Postconditioning Inhibits Apoptosis After Focal Cerebral Ischemia/Reperfusion Injury in the Rat
Stroke, August 1, 2008; 39(8): 2362 - 2369.
[Abstract] [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
 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
 Cardiovasc ResHome page
Z.-Q. Zhao and J. Vinten-Johansen
Postconditioning: Reduction of reperfusion-induced injury
Cardiovasc Res, May 1, 2006; 70(2): 200 - 211.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract 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 Bopassa, J.-C.
Right arrow Articles by Ovize, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bopassa, J.-C.
Right arrow Articles by Ovize, M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?