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Am J Physiol Heart Circ Physiol 288: H971-H976, 2005. First published September 9, 2004; doi:10.1152/ajpheart.00374.2004
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Ischemic preconditioning protects by activating prosurvival kinases at reperfusion

Derek J. Hausenloy, A. Tsang, Mihaela M. Mocanu, and Derek M. Yellon

The Hatter Institute, University College London Hospital, London, United Kingdom

Submitted 19 April 2004 ; accepted in final form 26 August 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Pharmacological activation of the prosurvival kinases Akt and ERK-1/2 at reperfusion, after a period of lethal ischemia, protects the heart against ischemia-reperfusion injury. We hypothesized that ischemic preconditioning (IPC) protects the heart by phosphorylating the prosurvival kinases Akt and ERK-1/2 at reperfusion. In isolated perfused Sprague-Dawley rat hearts subjected to 35 min of lethal ischemia, the phosphorylation states of Akt, ERK-1/2, and p70 S6 kinase (p70S6K) were determined after 15 min of reperfusion, and infarct size was measured after 120 min of reperfusion. IPC induced a biphasic response in Akt and ERK-1/2 phosphorylation during the preconditioning and reperfusion phases after the period of lethal ischemia. IPC induced a fourfold increase in Akt, ERK-1/2, and p70S6K phosphorylation at reperfusion and reduced the infarct risk-to-volume ratio (56.9 ± 5.7 and 20.9 ± 3.6% for control and IPC, respectively, P < 0.01). Inhibiting the IPC-induced phosphorylation of Akt, ERK-1/2, and p70S6K at reperfusion with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY-294002 or the MEK-1/2 inhibitor PD-98059 abrogated IPC-induced protection (46.3 ± 5.8, 49.2 ± 4.0, and 20.9 ± 3.6% for IPC + LY-294002, IPC + PD-98059, and IPC, respectively, P < 0.01), demonstrating that the phosphorylation of these kinases at reperfusion is required for IPC-induced protection. In conclusion, we demonstrate that the reperfusion phase following sustained ischemia plays an essential role in mediating IPC-induced protection. Specifically, we demonstrate that IPC protects the heart by phosphorylating the prosurvival kinases Akt and ERK-1/2 at reperfusion.

mitogen-activated protein kinases; phosphatidylinositol 3-kinase-Akt; myocardial infarction; reperfusion injury

TRANSIENT EPISODES of nonlethal ischemia and reperfusion confer profound protection on the myocardium in response to a prolonged lethal episode of ischemia-reperfusion, a phenomenon that has been termed ischemic preconditioning (IPC) (11). Studies have demonstrated that, after a lethal episode of ischemia, the pharmacological phosphorylation of certain prosurvival kinases, such as phosphatidylinositol 3-kinase (PI3K)-Akt and the mitogen-activated protein kinase p42/p44 extracellular signal-regulated kinases 1 and 2 (ERK-1/2), at reperfusion protects the heart against ischemia-reperfusion injury (7). In addition, it appears that there exists a complex interplay or "cross talk" between these two kinase cascades, at reperfusion, in the execution of their cardioprotective effects (5).

Interestingly, we recently demonstrated that the PI3K-Akt and MEK-1/2-ERK-1/2 kinases, which we have termed the reperfusion injury salvage kinase pathway (7), are phosphorylated at reperfusion in response to an IPC stimulus (5). However, whether their phosphorylation at reperfusion is required for IPC-induced protection is unknown. Although previous studies have shown that the phosphorylation of the PI3K-Akt (10, 15) and MEK-1/2-ERK-1/2 (3) kinase cascades occurs in the setting of IPC, these studies investigated the phosphorylation of these kinases during the preconditioning phase.

In the present study, we examine events during the reperfusion phase in the setting of IPC. We hypothesize that the phosphorylation of the PI3K-Akt and MEK-1/2-ERK-1/2 kinase cascades, which occurs at reperfusion, in response to the IPC stimulus is essential for IPC-induced protection.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Male Sprague-Dawley rats (300 ± 50 g body wt; Charles River, Margate, UK) received humane care in accordance with the Guidance on the Operation of the Animals (Scientific Procedures) Act 1986 (The Stationery Office, London, UK).

Isolated perfused rat heart. Excised rat hearts were Langendorff perfused with Krebs-Henseleit buffer and subjected to 35 min of regional ischemia followed by 1) 120 min of reperfusion, after which the infarct risk-to-volume ratio was determined by triphenyltetrazolium chloride staining (n = 6/group) (4), or 2) 15 min of reperfusion, after which samples taken from the region at risk were snap frozen for subsequent Western blot analysis for Akt, ERK-1/2, and p70 S6 kinase (p70S6K) phosphorylation (n = 6/group) (10). In both protocols, the risk zone was delineated by Evans blue staining of the nonrisk zone.

Isolated rat hearts were randomly assigned to the following treatment groups (Fig. 1). Group 1 consisted of control hearts. Group 2 consisted of IPC hearts subjected to two 5-min periods of global ischemia and 10-min periods of reperfusion before the lethal ischemic insult. Groups 3 and 4 consisted of IPC hearts treated with LY-294002 (15 µmol/l; Tocris), a PI3K inhibitor, PD-98059 (10 µmol/l, Tocris), an MEK-1/2 inhibitor, or DMSO vehicle controls for the first 15 min of reperfusion following the period of lethal ischemia. These concentrations of kinase inhibitors have been demonstrated to result in inhibition of Akt and ERK-1/2 phosphorylation in the isolated perfused rat heart (10). Groups 5 and 6 were control hearts that were treated with LY-294002 or PD-98059 alone for the first 15 min of reperfusion.



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  		Fig. 1. Experimental protocols for isolated perfused rat heart studies. TTC, triphenyltetrazolium chloride; LY, LY-294002; PD, PD-98059.

 
Time course of Akt and ERK-1/2 phosphorylation induced by IPC. Control and IPC hearts were subjected to ischemia-reperfusion, and samples were taken from the region at risk and snap frozen at the following time points (n = 6 hearts at each time point) for subsequent Western blot analysis for Akt and ERK-1/2 phosphorylation (Fig. 1): 1) at the end of stabilization or the IPC protocol, just before lethal ischemia; 2) after 15 min of lethal ischemia; 3) at the end of 35 min of lethal ischemia; and 4) after 15 min of reperfusion.

Western blot analysis. Equal amounts of protein (30 µg/sample) were electrophoresed on a 12.5% SDS-polyacrylamide gel, transferred to a nitrocellulose membrane (Amersham), and probed with antibodies (1:1,000; Cell Signalling) for phosphorylated and total ERK-1/2, Akt, and p70S6K (Thr389 and Thr421/Ser424). Coomassie blue and Ponceau red were used to verify adequate transfer of proteins from the gel to the membrane. {beta}-Actin was used to ensure equal protein loading. Proteins were detected using chemiluminescence, bands were visualized by exposure to photographic film, and relative densitometry was assessed using NIH Image 1.63 software (10).

Statistical analysis. Values are means ± SE. Data were analyzed using one-way analysis of variance and Fisher’s protected least significant difference test for multiple comparisons. P < 0.05 was considered significant.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
IPC induced a biphasic response in Akt and ERK-1/2 phosphorylation. IPC resulted in an immediate increase in Akt phosphorylation [relative density = 242.0 ± 31.8 and 680.7 ± 160.9 arbitrary units (AU) for control and IPC, respectively, P < 0.05; Fig. 2A], which declined during the period of lethal ischemia, followed by a second increase at reperfusion (563.7 ± 74.4 and 129.7 ± 33.9 AU for IPC and control, respectively, P < 0.001; Fig. 2A).



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  		Fig. 2. Representative Western blots and relative densities depicting time course of Akt phosphorylation (A) and ERK-1/2 phosphorylation (B) in control and ischemically preconditioned (IPC) rat hearts. IPC induces 2 phases of Akt and ERK-1/2 phosphorylation: immediately after the IPC protocol and at reperfusion. AU, arbitrary units. Values are means ± SE; n = 6. *P < 0.05.

 
IPC resulted in a similar biphasic response in ERK-1/2 phosphorylation: during the preconditioning phase (540.3 ± 130.2 and 804.2 ± 165.4 AU for control and IPC, respectively, P < 0.05; Fig. 2B) and at reperfusion (834.3 ± 14.1 and 275.8 ± 20.8 AU for IPC and control, respectively, P < 0.001; Fig. 2B).

In addition to inducing the phosphorylation of Akt and ERK-1/2 after 15 min of reperfusion (Fig. 3), IPC also resulted in the phosphorylation of p70S6K, the kinase downstream of Akt and ERK-1/2, at Thr389, the site phosphorylated by Akt-mammalian target of rapamycin (5925.5 ± 520.0 with IPC vs. 608.5 ± 100.1 in control; P < 0.01; Fig. 3A) and at Thr421 and Ser424, the sites phosphorylated by ERK-1/2 (5947.5 ± 904.5 with IPC vs. 1114.6 ± 292.7 in control; P < 0.01; Fig. 3B).



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  		Fig. 3. Representative Western blots and relative densities showing that inhibition of phosphatidylinositol 3-kinase (PI3K) with LY-294002 (A) or inhibition of MEK-1/2 with PD-98059 (B) abolishes IPC-induced phosphorylation of Akt and ERK-1/2 and their respective kinase-specific phosphorylation sites on p70 S6 kinase (p70S6K). Values are means ± SE; n = 6. *P < 0.05.

 
Inhibiting PI3K or MEK-1/2 at reperfusion abrogated IPC-induced phosphorylation of Akt, ERK-1/2, and p70S6K. The presence of LY-294002 (the PI3K inhibitor) during the first 15 min of reperfusion abrogated the IPC-induced phosphorylation of Akt (267.7 ± 60.5 with IPC + LY-294002 vs. 4428.8 ± 874.8 with IPC; P < 0.01; Fig. 3A), and p70S6K (Thr389; 350.3 ± 70.8 with IPC + LY-294002 vs. 5925.5 ± 520.0 with IPC; respectively, P < 0.01; Fig. 3A). The presence of PD-98059 (the MEK-1/2 inhibitor) during the first 15 min of reperfusion abrogated the IPC-induced phosphorylation of ERK-1/2 (3169.3 ± 281.6 in IPC + PD-98059 vs. 9082.5 ± 1250.5 in IPC; respectively, P < 0.01; Fig. 3B) and p70S6K (Thr421/Ser424; 2287.3 ± 349.0 in IPC + PD-98050 vs. 5947.5 ± 904.5 in IPC; respectively, P < 0.01; Fig. 3B).

LY-294002 or PD-98059, given alone at the time of reperfusion to control hearts, did not influence Akt phosphorylation (Fig. 3A), ERK-1/2 phosphorylation (Fig. 3B), p70S6K phosphorylation at Thr421/Ser424 (Fig. 3B), or Thr389 (Fig. 3A).

The levels of total Akt, ERK-1/2, and p70S6K did not vary with the stage of ischemia-reperfusion in the control setting or in the presence of IPC, suggesting that any changes in kinase phosphorylation were not due to changes in total kinase levels (Fig. 4).



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  		Fig. 4. A: representative Western blots depicting time course for total levels of Akt and ERK-1/2 in control and IPC hearts at stabilization (stab), 15 min of ischemia (isch), 35 min of ischemia, and 15 min of reperfusion (rep). There was no change in total kinase levels during ischemia-reperfusion in control or IPC-treated hearts. B: representative Western blots depicting total levels of Akt, ERK-1/2, and p70S6K in control and IPC hearts after 15 min of reperfusion. There was no change in total kinase levels in control or IPC-treated hearts in the presence or absence of LY-294002 or PD-98059. C: total {beta}-actin, demonstrating equal protein loading in all experimental groups.

 
Inhibiting Akt or ERK-1/2 phosphorylation at reperfusion abrogates IPC-mediated reduction in infarct size. IPC was cardioprotective, as evidenced by a reduction in infarct size from 56.9 ± 5.7% in control to 20.9 ± 3.6% with IPC (P < 0.01). The presence of LY-294002 (the PI3K inhibitor) or PD-98059 (the MEK-1/2 inhibitor) for the first 15 min of reperfusion abrogated the IPC-induced reduction in infarct size (46.3 ± 5.8, 49.2 ± 4.0, and 20.9 ± 3.6% for IPC + LY-294002, IPC + PD-98059, and IPC, respectively, P < 0.01). LY-294002 or PD-98059, given alone at the time of reperfusion to control hearts, did not influence infarct size (43.1 ± 7.2, 57.7 ± 7.0, and 56.9 ± 5.7% for LY-294002, PD-98059, and control, respectively, P = not significant).

DMSO vehicle (0.02%) did not influence infarct size or kinase phosphorylation.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
We report for the first time that IPC induces a biphasic response in Akt and ERK-1/2 phosphorylation, with the firstphase occurring immediately after the IPC stimulus and the second phase of Akt, ERK-1/2, and p70S6K activation occurring at reperfusion, after the lethal ischemic insult. Importantly, we demonstrate for the first time that IPC protects the heart against ischemia-reperfusion injury by modifying crucial events during the reperfusion phase that follows the index ischemic period. Specifically, we have shown that the phosphorylation of these kinases at reperfusion is essential for IPC-induced protection, inasmuch as inhibiting their phosphorylation during the first few minutes abrogated the IPC-mediated reduction in infarct size.

Previous studies have demonstrated that the pharmacologically induced phosphorylation of PI3K-Akt and MEK-1/2-ERK-1/2 in the first few minutes of reperfusion after a sustained ischemic insult is cardioprotective (7). In the present study, we demonstrate that the phosphorylation of these kinases at reperfusion is required for IPC-induced protection. Although previous studies have implicated these kinases in the setting of IPC (10, 15), the phosphorylation of these kinase cascades occurred during the preconditioning phase, with the kinases conveying the preconditioning signal to downstream mediators of preconditioning, such as PKC (15) and reactive oxygen species (ROS; Fig. 5) (9). Fryer and colleagues (3) also noted two phases of ERK-1/2 phosphorylation, although they did not examine whether the ERK-1/2 phosphorylation that occurred at reperfusion contributed to IPC-induced protection. It appears, therefore, that the phosphorylation of these kinase cascades is required during the preconditioning phase and at reperfusion to mediate IPC-induced protection (Fig. 5). Interestingly, our previous study demonstrated that the PI3K-Akt and MEK-1/2-ERK-1/2 kinase cascades exhibit cross talk, with one kinase cascade appearing to interact with and influence the other (5). This interplay between different kinases implicated in IPC was also observed between PKC and tyrosine kinase (17), suggesting a form of "compensatory regulation" between these different kinase cascades that allows the preconditioning signal to be executed, even if one of the kinases is inhibited.



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  		Fig. 5. Hypothetical scheme outlining the 2 phases of kinase cascade activation in response to IPC. During the preconditioning phase, mitochondrial reactive oxygen species (ROS) were released and PKC was activated. These events reactivate the PI3K-Akt-p70S6K and MEK-1/2-ERK-1/2-p70S6K cascades, which comprise the reperfusion injury salvage kinase (RISK) pathway, at reperfusion. The RISK pathway mediates cellular survival through several possible mechanisms, which may include inhibition of mitochondrial permeability transition pore (mPTP) opening.

 
The mechanism that mediates the phosphorylation of these kinases at the time of reperfusion in hearts subjected to IPC is unclear. We speculate that PKC, which has been implicated as an early mediator of the preconditioning signal (13), may contribute to the phosphorylation of Akt and ERK-1/2 at the time of reperfusion, inasmuch as studies suggest that PKC can phosphorylate these kinase cascades (Fig. 5) (12). Whether ROS contribute to the phosphorylation of these kinase cascades at the time of reperfusion is unclear. On the one hand, the time course of ROS production in IPC-treated hearts reported in a recent study (8) appears to correlate with the time course of kinase phosphorylation demonstrated in the present study, and ROS have been shown to phosphorylate the kinase cascades at reperfusion (14). On the other hand, IPC has been demonstrated to reduce ROS production at reperfusion (2). Furthermore, we speculate that, at reperfusion, these kinases may protect the heart by inhibiting the opening of the mitochondrial permeability transition pore (mPTP; Fig. 5), which is a critical determinant of cell death in ischemia-reperfusion injury (6). These kinases may inhibit mPTP opening by 1) preventing the translocation of the mPTP-inducing proapoptotic protein Bax to the mitochondria (16) or 2) activating endothelial nitric oxide synthase, which may inhibit mPTP opening via nitric oxide (1).

In conclusion, we report that IPC results in the phosphorylation of the PI3K-Akt and MEK-1/2-ERK-1/2 pathways during the reperfusion phase after lethal ischemia, and we demonstrate that these kinases are essential for IPC-induced protection. Importantly, we have demonstrated that IPC protects the heart by modifying crucial events during the reperfusion phase. Pharmacological activation of these kinases at reperfusion may therefore deliver the protection associated with IPC in the clinical arena of reperfusion. It had been thought that IPC or preconditioning mimetics needed to be given before ischemia to effect a positive result. We believe that it is now possible to target the reperfusion phase, which is both clinically desirable and practical.


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This work was supported by the British Heart Foundation.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. M. Yellon, The Hatter Institute, Univ. College London Hospital, Grafton Way, London WC1E 6DB, UK (E-mail: hatter-institute{at}ucl.ac.uk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 

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  3. Fryer RM, Pratt PF, Hsu AK, and Gross GJ. Differential activation of extracellular signal-regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. J Pharmacol Exp Ther 296: 642–649, 2001.[Abstract/Free Full Text]
  4. Hausenloy DJ, Maddock HL, Baxter GF, and Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning? Cardiovasc Res 55: 534–543, 2002.[Abstract/Free Full Text]
  5. Hausenloy DJ, Mocanu MM, and Yellon DM. Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning. Cardiovasc Res 63: 305–312, 2004.[Abstract/Free Full Text]
  6. Hausenloy DJ and Yellon DM. The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 35: 339–341, 2003.[CrossRef][ISI][Medline]
  7. Hausenloy DJ and Yellon DM. New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK) pathway. Cardiovasc Res 61: 448–460, 2004.[Abstract/Free Full Text]
  8. Kevin LG, Camara AK, Riess ML, Novalija E, and Stowe DF. Ischemic preconditioning alters real-time measure of O2 radicals in intact hearts with ischemia and reperfusion. Am J Physiol Heart Circ Physiol 284: H566–H574, 2003.[Abstract/Free Full Text]
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  13. Speechly-Dick ME, Mocanu MM, and Yellon DM. Protein kinase C. Its role in ischemic preconditioning in the rat. Circ Res 75: 586–590, 1994.[Abstract/Free Full Text]
  14. Takeishi Y, Abe J, Lee JD, Kawakatsu H, Walsh RA, and Berk BC. Differential regulation of p90 ribosomal S6 kinase and big mitogen-activated protein kinase 1 by ischemia/reperfusion and oxidative stress in perfused guinea pig hearts. Circ Res 85: 1164–1172, 1999.[Abstract/Free Full Text]
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N. Fulop, Z. Zhang, R. B. Marchase, and J. C. Chatham
Glucosamine cardioprotection in perfused rat hearts associated with increased O-linked N-acetylglucosamine protein modification and altered p38 activation
Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2227 - H2236.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
J.-X. Chen, H. Zeng, Q.-H. Tuo, H. Yu, B. Meyrick, and J. L. Aschner
NADPH oxidase modulates myocardial Akt, ERK1/2 activation, and angiogenesis after hypoxia-reoxygenation
Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1664 - H1674.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
R. M. Bell, J. E. Clark, D. J. Hearse, and M. J. Shattock
Reperfusion kinase phosphorylation is essential but not sufficient in the mediation of pharmacological preconditioning: Characterisation in the bi-phasic profile of early and late protection
Cardiovasc Res, January 1, 2007; 73(1): 153 - 163.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
J. D. Joo, M. Kim, V. D. D'Agati, and H. T. Lee
Ischemic Preconditioning Provides Both Acute and Delayed Protection against Renal Ischemia and Reperfusion Injury in Mice
J. Am. Soc. Nephrol., November 1, 2006; 17(11): 3115 - 3123.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Nishihara, T. Miura, T. Miki, J. Sakamoto, M. Tanno, H. Kobayashi, Y. Ikeda, K. Ohori, A. Takahashi, and K. Shimamoto
Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3beta
Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H748 - H755.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
L. Bertrand, A. Ginion, C. Beauloye, A. D. Hebert, B. Guigas, L. Hue, and J.-L. Vanoverschelde
AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B
Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H239 - H250.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
M. Khan, S. Varadharaj, L. P. Ganesan, J. C. Shobha, M. U. Naidu, N. L. Parinandi, S. Tridandapani, V. K. Kutala, and P. Kuppusamy
C-phycocyanin protects against ischemia-reperfusion injury of heart through involvement of p38 MAPK and ERK signaling
Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2136 - H2145.
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 Cardiovasc ResHome page
D. J. Hausenloy and D. M. Yellon
Survival kinases in ischemic preconditioning and postconditioning
Cardiovasc Res, May 1, 2006; 70(2): 240 - 253.
[Abstract] [Full Text] [PDF]

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 Cardiovasc ResHome page
D. Garcia-Dorado, A. Rodriguez-Sinovas, M. Ruiz-Meana, J. Inserte, L. Agullo, and A. Cabestrero
The end-effectors of preconditioning protection against myocardial cell death secondary to ischemia-reperfusion
Cardiovasc Res, May 1, 2006; 70(2): 274 - 285.
[Abstract] [Full Text] [PDF]

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 Physiol. GenomicsHome page
E. Lucchinetti, J. Feng, R. d. Silva, G. V. Tolstonog, M. C. Schaub, G. G. Schumann, and M. Zaugg
Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling
Physiol Genomics, April 13, 2006; 25(2): 314 - 324.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
L. M. Schwartz and C. J. Lagranha
Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs
Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1011 - H1018.
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 J. Thorac. Cardiovasc. Surg.Home page
I. E. Konstantinov, J. Li, and A. N. Redington
From mesothelioma to cardiovascular protection via the phosphoinositide-3 kinase pathway: A new vista in cardiothoracic surgery
J. Thorac. Cardiovasc. Surg., February 1, 2006; 131(2): 509 - 510.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
K. Przyklenk, M. Maynard, and P. Whittaker
Reduction of infarct size with D-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial KATP channels
Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H830 - H836.
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 CirculationHome page
S. Lecour, N. Suleman, G. A. Deuchar, S. Somers, L. Lacerda, B. Huisamen, and L. H. Opie
Pharmacological Preconditioning With Tumor Necrosis Factor-{alpha} Activates Signal Transducer and Activator of Transcription-3 at Reperfusion Without Involving Classic Prosurvival Kinases (Akt and Extracellular Signal-Regulated Kinase)
Circulation, December 20, 2005; 112(25): 3911 - 3918.
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 J. Physiol.Home page
D. A. Brown, A. J. Chicco, K. N. Jew, M. S. Johnson, J. M. Lynch, P. A. Watson, and R. L. Moore
Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel in the rat
J. Physiol., December 15, 2005; 569(3): 913 - 924.
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 Br J AnaesthHome page
J. Raphael, J. Rivo, and Y. Gozal
Isoflurane-induced myocardial preconditioning is dependent on phosphatidylinositol-3-kinase/Akt signalling
Br. J. Anaesth., December 1, 2005; 95(6): 756 - 763.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Tsang, D. J. Hausenloy, and D. M. Yellon
Myocardial postconditioning: reperfusion injury revisited
Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H2 - H7.
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 J Am Coll CardiolHome page
K. Mensah, M. M. Mocanu, and D. M. Yellon
Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: A potential role for phosphatase and tensin homolog deleted on chromosome ten?
J. Am. Coll. Cardiol., April 19, 2005; 45(8): 1287 - 1291.
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