doi: 10.1161/CIRCULATIONAHA.108.805242
(Circulation. 2008;118:1915-1919.)
© 2008 American Heart Association, Inc.
Editorial |
Cardioprotection
Nitric Oxide, Protein Kinases, and Mitochondria
From the Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany.
Correspondence to Prof Dr med Dr hc Gerd Heusch, FRCP, Direktor des Instituts für Pathophysiologie, Universitätsklinikum Essen, Hufelandstr 55, 45122 Essen, Germany. E-mail gerd.heusch{at}uk-essen.de
Key Words: Editorials • ischemia • nitric oxide • nitric oxide synthase • reperfusion • signal transduction
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Introduction |
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 Top Introduction Stunning Versus Hibernation...Cardioprotective SignalingNO: Trigger, Mediator, Potential...Protein Kinase Activation in...Mitochondrial Targets of...References |
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Over the past 2 to 3 decades, several phenomena have been identified that provide powerful protection against myocardial infarction and other sequelae of ischemia/reperfusion1: myocardial hibernation that is related to stunning,2 ischemic preconditioning,3 delayed or second-window ischemic preconditioning,4 ischemic postconditioning,5 and their pharmacological recruitment. Stunning and hibernation share contractile function as an end point. In stunning, reduced postischemic contractile function is viewed as reversible injury, whereas in hibernation dysfunction is viewed as an adaptive response. Ischemic preconditioning is characterized by infarct size reduction as its most robust end point but shares with hibernation the underlying idea of a regulated protective response. These phenomena have been confirmed in patients with coronary artery disease.2,6–8 Nitric oxide (NO) and mitochondria also are important in patients with coronary artery disease. Nitroglycerin induces delayed protection against periinterventional ischemic ECG alterations, contractile dysfunction, and pain sensation,7 and cyclosporin A, which inhibits opening of the mitochondrial permeability transition pore (MPTP), attenuates reperfusion injury in patients with acute myocardial infarction.9
Articles pp 1961 and 1970
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Stunning Versus Hibernation Versus Preconditioning: What Is the Difference? |
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TopIntroductionStunning Versus Hibernation...Cardioprotective SignalingNO: Trigger, Mediator, Potential...Protein Kinase Activation in...Mitochondrial Targets of...References |
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The "new ischemic syndromes" have intrigued scientists and clinicians trying to understand their underlying pathophysiology and to recruit their cardioprotective potential. This initial enthusiasm has not materialized into translational medicine.10 Why is that? There has been a long but ultimately fruitless debate as to whether the phenotype of hibernating myocardium is the result of ongoing ischemia with reduced baseline coronary blood flow or repetitive cycles of ischemia/reperfusion and consequent stunning without reduced baseline flow. Clearly, perfusion-contraction matching cannot be maintained for >12 hours. Conversely, repetitive cycles of ischemia/reperfusion with subsequent stunning finally result in hibernating myocardium with reduced contractile function and baseline blood flow.2 Thus, the cumulative effect of stunning is a progression to hibernation. True stunning, if seen at all, is rare, modest, and, apart from its paradigmatic value, important only in its cumulative manifestation as hibernation.6 Chronic, reversible contractile dysfunction also results from coronary microembolization in which small microinfarcts initiate an inflammatory process, including increased expression of tumor necrosis factor-
.11 Upregulated cardioprotective gene and protein programs were identified in preconditioned and hibernating myocardium of animals and humans,12,13 thus making the distinction between hibernation and preconditioning more ambiguous.
The report by Shen et al14 in this issue of Circulation further undermines the artificial distinction between stunning, hibernation, and preconditioning. In chronically instrumented pigs, 6 cycles of severe coronary stenosis with subsequent reperfusion did not induce necrosis but did result in profound contractile dysfunction. Repetitive coronary stenosis also resulted in the upregulation of potentially protective proteins and reduced infarct size from complete coronary occlusion and reperfusion. In other words, a protocol of cumulative stunning induced the phenotype of hibernating myocardium that was preconditioned. The transcripts of genes encoding proteins involved in cell cycle control and autophagy were upregulated in the myocardium at risk with this repeated coronary stenosis but not with a delayed preconditioning protocol. Protein kinase C (PKC)-
was not translocated to the particulate fraction, and NO synthase (NOS) activity was not increased, which again was different from delayed preconditioning. In pigs, however, the isoform of PKC is more important in preconditioning than the isoform,15 and the lack of effect of NOS blockade does not exclude an important role for NO.16 A causal role for the differentially expressed gene and protein program was not established, largely because of the only retrospective tissue sampling and the non–hypothesis-driven nature of such a genomic approach. Unfortunately, the study did not address inflammatory signals such as tumor necrosis factor-, which protects from infarction several hours after coronary microembolization.11
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Cardioprotective Signaling |
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TopIntroductionStunning Versus Hibernation...Cardioprotective SignalingNO: Trigger, Mediator, Potential...Protein Kinase Activation in...Mitochondrial Targets of...References |
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In this issue of Circulation, West et al17 address the interaction of NO with mitochondria in effecting cardioprotection. Using mice with cardiomyocyte-specific constitutive overexpression of inducible NOS (iNOS), they confirm the NO hypothesis of delayed preconditioning as originally proposed by Bolli et al18 and extend it by demonstrating sustained protection by iNOS overexpression. They attribute protection by iNOS overexpression or pretreatment with an NO donor to inhibition of MPTP opening. Multiple end points of protection, notably infarct size in situ and ex vivo, functional recovery, and reactive oxygen species (ROS) formation ex vivo, were measured. Three different methods were used to determine MPTP opening in isolated mitochondria, and the results were confirmed by nicotinamide dinucleotide (NAD+) loss in ex vivo hearts. The MPTP opener atractyloside did not abolish protection in iNOS-overexpressing hearts. The classic MPTP inhibitor cyclosporin A induced disparate effects; it increased ROS formation on reperfusion but improved functional recovery. Cyclosporin A also decreased cytochrome c release into the cytosol but did not affect mitochondrial deoxyglucose retention. The atractyloside and cyclosporin A data are somewhat difficult to reconcile, but the authors’ explanation of an NO action somewhere upstream of MPTP appears plausible. The mechanistic strength of the present study notwithstanding, important questions remain: What is the role of the other enzymes that are upregulated in delayed preconditioning (cyclooxygenase 2, manganese superoxide dismutase, aldose reductase18), and how do they relate to MPTP opening? Which other proteins are upregulated or downregulated in cardiomyocytes with constitutive iNOS overexpression, and what is their role in cardioprotection? The phenotype of the iNOS-overexpressing mice is not entirely innocuous; they have mild left ventricular hypertrophy, contractile dysfunction, and alterations in respiratory chain complexes.
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NO: Trigger, Mediator, Potential Effector of Cardioprotection |
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TopIntroductionStunning Versus Hibernation...Cardioprotective SignalingNO: Trigger, Mediator, Potential...Protein Kinase Activation in...Mitochondrial Targets of...References |
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NO at low concentration increases ventricular function19 and matches myocardial oxygen consumption to contractile function in short-term hibernating myocardium;20 NO at high concentration triggers inflammation and suppresses contractile function.21 Exogenous NO triggers preconditioning, whereas NOS-derived endogenous NO is not important for classic ischemic preconditioning.21 Endogenous NO is both a trigger (through endothelial NOS) and a mediator (through iNOS) of delayed ischemic preconditioning.18 In addition, ischemic postconditioning uses NO as a signal.22 Apart from the specific NOS isoform that generates NO and its cellular (endothelium, cardiomyocyte, leukocyte, etc) and subcellular (cytosol, caveolae, etc) localization, significant amounts of NO are formed nonenzymatically during myocardial ischemia,16 so negative findings using pharmacological NOS blockade do not rule out an important role for endogenous NO.
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Protein Kinase Activation in Cardioprotection |
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TopIntroductionStunning Versus Hibernation...Cardioprotective SignalingNO: Trigger, Mediator, Potential...Protein Kinase Activation in...Mitochondrial Targets of...References |
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A variety of protein kinases are activated and interact at multiple levels and at various time points during ischemia/reperfusion. Three different cardioprotective protein kinase programs have been proposed (Figure). The first program is recruited during the trigger and mediator phase of acute ischemic preconditioning and is shown in Figure, A. After activation of G-protein–coupled receptors by adenosine, bradykinin, opioids, urocortins, etc,23 or of receptors for peptides such as natriuretic peptides,24 PKC is directly activated (only through adenosine) or phosphoinositide 3 kinase (PI3K)/Akt is activated with further downstream activation of endothelial NOS and NO formation, guanylate cyclase activation, protein kinase G (PKG) and PKC activation; this leads to the activation of the mitochondrial ATP-dependent K channel (KATP) and ROS formation, resulting in p38 mitogen-activated kinase and PKC activation23,25 and priming of MPTP for opening.26 The second program is recruited during early reperfusion with the execution phase of acute ischemic preconditioning and with ischemic postconditioning and is shown in Figure, B. Activation of sarcolemmal G-protein–coupled receptors or of receptors for growth factors results in activation of the reperfusion injury salvage kinase (RISK) program. RISK involves the parallel activation of the PI3K/Akt and the extracellular regulated kinase system with downstream p70 ribosomal protein S6 kinase (p70S6K) and glycogen synthase kinase 3β (GSK3β) activation and the ultimate inhibition of MPTP opening.27 The role of specific RISKs in protection is contentious.28,29 The third program is recruited with acute ischemic preconditioning, delayed ischemic preconditioning, and ischemic postconditioning and is shown in Figure, C. After activation of sarcolemmal glycoprotein 130 (gp130) receptors or tumor necrosis factor-
receptors, the janus-activated kinase (JAK) signal transducer and activator of transcription (STAT) pathway is activated with projection to the nucleus and possibly to mitochondria.28,30 In program A, NO is a central step; in program B, NO is in a side line, with endothelial NOS activation by Akt; and in program C, NO is somewhere upstream of tumor necrosis factor- formation31 and a product of iNOS. The isoform of p38 mitogen-activated protein kinase contributes to ischemia/reperfusion damage, and its β isoform is a target of ROS and contributes to protection by ischemic preconditioning.15,32 The cell cycle kinase H11 is in a side line with Akt and upregulated in protected myocardium.12
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Mitochondrial Targets of Cardioprotection and Their Interaction With Protein Kinases and NO |
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TopIntroductionStunning Versus Hibernation...Cardioprotective SignalingNO: Trigger, Mediator, Potential...Protein Kinase Activation in...Mitochondrial Targets of...References |
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Mitochondria are the major site of cellular energy/ATP production. The respiratory chain accepts electrons from NADH/H and flavine adenine dinucleotide (FADH)/H and transports them over 4 complexes ultimately onto oxygen, creating a proton gradient that then drives ATP production. Apart from ATP production and its role in cell function and survival, mitochondria are decisive elements for cell death by apoptosis, autophagy, and necrosis and, conversely, are targets for protection from cell death by several of the above kinases (PKC, PKG, GSK3β) and for NO (the Table).33
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Respiratory Chain
Respiratory chain proteins are downregulated in repetitively14 or chronically13 poststenotic myocardium. ADP-stimulated respiration is reduced by ischemia. Ischemic preconditioning does not prevent this reduction.34 The respiratory chain releases small amounts of ROS predominantly by complex I under physiological conditions.35 Partial uncoupling of the respiratory chain protects against ischemia/reperfusion injury similar to preconditioning, supporting the importance of mitochondrial ROS for cardioprotection. During early reperfusion, ROS formation from various sources, including the respiratory chain, is largely augmented. Reversible inhibition of complex I by S-nitrosation (NO-mediated modification of thiols) is cardioprotective by limiting excess ROS formation during reperfusion.36
Uncoupling proteins in the inner membrane mediate a leakage of protons back into the matrix and thereby accelerate oxygen consumption. Delayed ischemic preconditioning is associated with upregulation of uncoupling proteins, and mitochondria with upregulated uncoupling proteins have diminished ROS formation.37
Mitochondrial KATP Channel
The KATP channel in the inner membrane is inhibited by ATP and activated by PKC and PKG. The exact molecular composition of the KATP channel and the participation of the sulfonylurea receptor subunit SUR2A and the potassium channel proteins Kir6.1 and 6.2 remain elusive. A purified inner membrane fraction, including the adenine nucleotide transporter and succinate dehydrogenase, confers KATP channel activity and is targeted by KATP agonist/antagonist drugs.38 Mitochondrial KATP channels are causally involved in ischemic preconditioning and postconditioning.39,40 However, insight into their exact function in cardioprotection is difficult because their molecular structure is still unclear, they have not yet been identified in cardiomyocytes by patch-clamp techniques, and pharmacological agents such as diazoxide (agonist) and 5-hydroxydecanoate (antagonist) are not specific.41 Mitochondrial KATP channel opening induces potassium and accompanying water flux along the electrochemical gradient, resulting in matrix swelling. The influx of potassium also triggers modest ROS formation by respiratory chain complex I, activating, in turn, PKC and p38 mitogen-activated protein kinase.25 NO induces mitochondrial KATP opening in a PKC-dependent25 or -independent mechanism that is still not defined.42
Connexin 43
Connexin 43 is present at the inner mitochondrial membrane of cardiomyocytes.43 Reduction of connexin 43 abolishes the cardioprotection by ischemic preconditioning44 but not postconditioning.45 ROS formation and cardioprotection in response to diazoxide depend on mitochondrial connexin 43, suggesting that its function is to regulate the gating of mitochondrial KATP channels.46 Mitochondrial connexin 43 is targeted by several protein kinases, including GSK3β.45
Mitochondrial Permeability Transition Pore
The MPTP is a large-conductance megachannel putatively constituted by the voltage-dependent anion channel in the outer membrane, the adenine nucleotide transporter in the inner membrane, and cyclophilin D in the matrix.35 Under physiological conditions, MPTP is predominantly in a closed state. Opening of the pore is favored by high concentrations of Ca2+, ROS, inorganic phosphate, and NO and a reduction of the inner membrane potential. All of these conditions occur during ischemia and reperfusion. The opening of the MPTP results in depolarization of the membrane potential and matrix swelling. This leads to rupture of the outer membrane and release of proteins such as cytochrome c from the intermembrane space into the cytosol. Mitochondria and sarcoplasmic reticulum interact, and the mitochondrial Ca2+ concentration during early reperfusion is determined by sarcoplasmic reticulum–dependent Ca2+ oscillations in the cytosol.47 Cyclosporin A blocks the enzymatic activity of cyclophilin D, inhibits MPTP opening, and attenuates reperfusion injury.9,35
Antioxidant Defense
Aldose reductase metabolizes toxic aldehydes, which are generated by lipid peroxidation and contribute to cell death. It is localized in the cytosol; however, it translocates in a PKC-dependent mechanism into mitochondria. Delayed ischemic preconditioning is known to increase aldose reductase protein and activity, and inhibition of its activity abolishes protection by delayed preconditioning.48 Manganese superoxide dismutase in the matrix catalyzes the reaction of superoxide to H2O2 and oxygen. Delayed ischemic preconditioning upregulates manganese superoxide dismutase and decreases ROS.18 Glutathione peroxidase, another ROS detoxifying enzyme, consumes glutathione to form hydrogen peroxide. Glutathione, however, reacts with NO to form S-nitrosoglutathione, which, during its degradation, may form glutathionyl radicals and subsequently ROS.49
The apparent paradox that characterizes both ischemic preconditioning and postconditioning, ie, a little ischemia/reperfusion before or after sustained ischemia/reperfusion protects, also is found at the signaling level for ROS, MPTP, and NO. Whereas high levels of ROS are detrimental for cardiomyocytes, moderate levels of ROS function as signaling molecules for cardioprotection by activating protein kinases. Likewise, inhibition of MPTP opening is cardioprotective, but transient opening of MPTP is required for cardioprotection.50 MPTP opening depends on NO. Low levels of NO prevent MPTP opening, whereas high NO levels accelerate MPTP opening and cytochrome c release.36 Part of the apparent paradox may be methodological in nature. Subsarcolemmal and interfibrillar mitochondria differ in their morphology and function. It is possible that sarcolemmal mitochondria serve a signaling function, whereas interfibrillar mitochondria are targets of damage and protection from it.
Apart from the translational gap from mice to humans, we need to know more about fundamental cardioprotective signaling. Do not take NO for the answer (yet).
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionStunning Versus Hibernation...Cardioprotective SignalingNO: Trigger, Mediator, Potential...Protein Kinase Activation in...Mitochondrial Targets of...References |
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1. Skyschally A, Schulz R, Heusch G. Pathophysiology of myocardial infarction: protection by ischemic pre- and postconditioning. Herz. 2008; 33: 88–100.[CrossRef][Medline] [Order article via Infotrieve]
2. Heusch G, Schulz R, Rahimtoola SH. Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol. 2005; 288: H984–H999.
3. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74: 1124–1136.
4. Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation. 1993; 88: 1264–1272.
5. Zhao Z-Q, Corvera JS, Halkos ME, Kerendi F, Wang N-P, Guyton RA, Vinten-Johansen J. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol. 2003; 285: H579–H588.
6. Heusch G. Stunning: great paradigmatic, but little clinical importance. Basic Res Cardiol. 1998; 93: 164–166.[CrossRef][Medline] [Order article via Infotrieve]
7. Heusch G. Nitroglycerin and delayed preconditioning in humans: yet another new mechanism for an old drug? Circulation. 2001; 103: 2876–2878.
8. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit J-F, Bonnefoy E, Finet G, Andre-Fouet X, Ovize M. Postconditioning the human heart. Circulation. 2005; 112: 2143–2148.
9. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D, Macia C, Raczka F, Sportouch C, Gahide G, Finet G, Andre-Fouet X, Revel D, Kirkorian G, Monassier J-P, Derumeaux G, Ovize M. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008; 359: 473–481.
10. Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA. Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res. 2004; 95: 125–134.
11. Skyschally A, Leineweber K, Gres P, Haude M, Erbel R, Heusch G. Coronary microembolization. Basic Res Cardiol. 2006; 101: 373–382.[CrossRef][Medline] [Order article via Infotrieve]
12. Depre C, Kim S-J, John AS, Huang Y, Rimoldi OE, Pepper JR, Dreyfus GD, Gaussin V, Pennell DJ, Vatner DE, Camici PG, Vatner SF. Program of cell survival underlying human and experimental hibernating myocardium. Circ Res. 2004; 95: 433–440.
13. Page B, Young R, Iyer V, Suzuki G, Lis M, Korotchkina L, Patel MS, Blumenthal KM, Fallavollita JA, Canty JM Jr. Persistent regional downregulation in mitochondrial enzymes and upregulation of stress proteins in swine with chronic hibernating myocardium. Circ Res. 2008; 102: 103–112.
14. Shen Y-T, Depre C, Yan L, Park JY, Tian B, Jain K, Chen L, Zhang Y, Kudej RK, Zhao X, Sadoshima J, Vatner DE, Vatner SF. Repetitive ischemia by coronary stenosis induces a novel window of ischemic preconditioning. Circulation. 2008; 118: 1961–1969.
15. Schulz R, Gres P, Skyschally A, Duschin A, Belosjorow S, Konietzka I, Heusch G. Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J. 2003; 17: 1355–1357.
16. Martin C, Schulz R, Post H, Boengler K, Kelm M, Kleinbongard P, Gres P, Skyschally A, Konietzka I, Heusch G. Microdialysis-based analysis of interstitial NO in situ: NO synthase-independent NO formation during myocardial ischemia. Cardiovasc Res. 2007; 74: 46–55.
17. West MB, Rokosh G, Obal D, Velayutham M, Xuan Y-T, Hill BG, Keith RJ, Schrader J, Guo Y, Conklin DJ, Prabhu SD, Zweier JL, Bolli R, Bhatnagar A. Cardiac myocyte–specific expression of inducible nitric oxide synthase protects against ischemia/reperfusion injury by preventing mitochondrial permeability transition. Circulation. 2008; 118: 1970–1978.
18. Bolli R, Li QH, Tang XL, Guo Y, Xuan YT, Rokosh G, Dawn B. The late phase of preconditioning and its natural clinical application: gene therapy. Heart Fail Rev. 2007; 12: 189–199.[CrossRef][Medline] [Order article via Infotrieve]
19. Rassaf T, Poll LW, Brouzos P, Lauer T, Totzeck M, Kleinbongard P, Gharini P, Andersen K, Schulz R, Heusch G, Mödder U, Kelm M. Positive effects of nitric oxide on left ventricular function in humans. Eur Heart J. 2006; 27: 1699–1705.
20. Heusch G, Post H, Michel MC, Kelm M, Schulz R. Endogenous nitric oxide and myocardial adaptation to ischemia. Circ Res. 2000; 87: 146–152.
21. Schulz R, Kelm M, Heusch G. Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res. 2004; 61: 402–413.
22. Penna C, Cappello S, Mancardi D, Raimondo S, Rastaldo R, Gattullo D, Losano G, Pagliario P. Post-conditioning reduces infarct size in the isolated rat heart: role of coronary flow and pressure and the nitric oxide/cGMP pathway. Basic Res Cardiol. 2006; 101: 168–179.[CrossRef][Medline] [Order article via Infotrieve]
23. Downey JM, Davis AM, Cohen MV. Signaling pathways in ischemic preconditioning. Heart Fail Rev. 2007; 12: 181–188.[CrossRef][Medline] [Order article via Infotrieve]
24. Burley DS, Hamid SA, Baxter GF. Cardioprotective actions of peptide hormones in myocardial ischemia. Heart Fail Rev. 2007; 12: 279–291.[CrossRef][Medline] [Order article via Infotrieve]
25. Costa AD, Garlid KD. Intramitochondrial signaling: interactions among mitoKATP, PKC{epsilon}, ROS, and MPT. Am J Physiol Heart Circ Physiol. 2008; 295: H874–H882.
26. Weiss JN, Korge P, Honda HM, Ping P. Role of the mitochondrial permeability transition in myocardial disease. Circ Res. 2003; 93: 292–301.
27. Hausenloy DJ, Yellon DM. Reperfusion injury salvage kinase signalling: taking a RISK for cardioprotection. Heart Fail Rev. 2007; 12: 217–234.[CrossRef][Medline] [Order article via Infotrieve]
28. Lecour S, Suleman N, Deuchar GA, Somers S, Lacerda L, Huisamen B, Opie LH. 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. 2005; 112: 3911–3918.
29. Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol. 2008; 51: 1393–1398.
30. Boengler K, Hilfiker-Kleiner D, Drexler H, Heusch G, Schulz R. The myocardial JAK/STAT pathway: from protection to failure. Pharmacol Ther. 2008; 120: 172–185.[CrossRef][Medline] [Order article via Infotrieve]
31. Thielmann M, Dörge H, Martin C, Belosjorow S, Schwanke U, van de Sand A, Konietzka I, Büchert A, Krüger A, Schulz R, Heusch G. Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-, and sphingosine. Circ Res. 2002; 90: 807–813.
32. Bassi R, Heads R, Marber MS, Clark JE. Targeting p38-MAPK in the ischaemic heart: kill or cure? Curr Opin Pharmacol. 2008; 8: 141–146.[CrossRef][Medline] [Order article via Infotrieve]
33. Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008; 88: 581–609.
34. Boengler K, Gres P, Dodoni G, Konietzka I, Di LF, Heusch G, Schulz R. Mitochondrial respiration and membrane potential after low-flow ischemia are not affected by ischemic preconditioning. J Mol Cell Cardiol. 2007; 43: 610–615.[CrossRef][Medline] [Order article via Infotrieve]
35. Di Lisa F, Canton M, Menabo R, Kaludercic N, Bernardi P. Mitochondria and cardioprotection. Heart Fail Rev. 2007; 12: 249–260.[CrossRef][Medline] [Order article via Infotrieve]
36. Burwell LS, Brookes PS. Mitochondria as a target for the cardioprotective effects of nitric oxide in ischemia-reperfusion injury. Antioxid Redox Signal. 2008; 10: 579–599.[CrossRef][Medline] [Order article via Infotrieve]
37. Sack MN. Mitochondrial depolarization and the role of uncoupling proteins in ischemia tolerance. Cardiovasc Res. 2006; 72: 210–219.
38. Ardehali H, Chen Z, Ko Y, Majía-Alvarez R, Marbán E. Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. Proc Natl Acad Sci U S A. 2004; 101: 11880–11885.
39. Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol. 2003; 285: H921–H930.
40. Penna C, Rastaldo R, Mancardi D, Raimondo S, Cappello S, Gattullo D, Losano G, Pagliario P. Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol. 2006; 101: 180–189.[CrossRef][Medline] [Order article via Infotrieve]
41. O'Rourke B. Myocardial KATP channels in preconditioning. Circ Res. 2000; 87: 845–855.
42. Sasaki N, Sato T, Ohler A, O'Rourke B, Marban E. Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation. 2000; 101: 439–445.
43. Boengler K, Dodoni G, Ruiz-Meana M, Cabestrero A, Rodriguez-Sinovas A, Garcia-Dorado D, Gres P, Di Lisa F, Heusch G, Schulz R. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res. 2005; 67: 234–244.
44. Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R. Loss of ischemic preconditioning’s cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol. 2007; 292: H1764–H1769.
45. Schulz R, Boengler K, Totzeck A, Luo Y, Garcia-Dorado D, Heusch G. Connexin 43 in ischemic pre- and postconditioning. Heart Fail Rev. 2007; 12: 261–266.[CrossRef][Medline] [Order article via Infotrieve]
46. Heinzel FR, Luo Y, Li X, Boengler K, Buechert A, García-Dorado D, Di Lisa F, Schulz R, Heusch G. Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res. 2005; 97: 583–586.
47. Piper HM, Abdallah Y, Kasseckert S, Schlüter KD. Sarcoplasmic reticulum-mitochondrial interaction in the mechanism of acute reperfusion injury. Cardiovasc Res. 2008; 77: 234–236.
48. Shinmura K, Bolli R, Liu S-Q, Tang X-L, Kodani E, Xuan Y-T, Srivastava S, Bhatnagar A. Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning. Circ Res. 2002; 91: 240–246.
49. Steffen M, Sarkela TM, Gybina AA, Steele TW, Trasseth NJ, Kuehl D, Giulivi C. Metabolism of S-nitrosoglutathione in intact mitochondria. Biochem J. 2001; 356: 395–402.[CrossRef][Medline] [Order article via Infotrieve]
50. Hausenloy D, Wynne A, Duchen M, Yellon D. Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation. 2004; 109: 1714–1717.
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 Y. Wang, L. Tao, Y. Yuan, W. B. Lau, R. Li, B. L. Lopez, T. A. Christopher, R. Tian, and X.-L. Ma Cardioprotective effect of adiponectin is partially mediated by its AMPK-independent antinitrative action Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E384 - E391. [Abstract] [Full Text] [PDF]
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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]
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R. Schulz and G. Heusch Tumor Necrosis Factor-{alpha} and Its Receptors 1 and 2: Yin and Yang in Myocardial Infarction? Circulation, March 17, 2009; 119(10): 1355 - 1357. [Full Text] [PDF]
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 C. Yin, F. N. Salloum, and R. C. Kukreja A Novel Role of MicroRNA in Late Preconditioning: Upregulation of Endothelial Nitric Oxide Synthase and Heat Shock Protein 70 Circ. Res., March 13, 2009; 104(5): 572 - 575. [Abstract] [Full Text] [PDF]
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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]
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