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• W2007545368 abstract "Cell survival is critically dependent on the preservation of cellular bioenergetics. However, the metabolic mechanisms that confer resistance to injury are poorly understood. Phosphotransfer reactions integrate ATP-consuming with ATP-producing processes and could thereby contribute to the generation of a protective phenotype. Here, we used ischemic preconditioning to induce a stress-tolerant state and 18O-assisted31P nuclear magnetic resonance spectroscopy to capture intracellular phosphotransfer dynamics. Preconditioning of isolated perfused hearts triggered a redistribution in phosphotransfer flux with significant increase in creatine kinase and glycolytic rates. High energy phosphoryl fluxes through creatine kinase, adenylate kinase, and glycolysis in preconditioned hearts correlated tightly with post-ischemic functional recovery. This was associated with enhanced metabolite exchange between subcellular compartments, manifested by augmented transfer of inorganic phosphate from cellular ATPases to mitochondrial ATP synthase. Preconditioning-induced energetic remodeling protected cellular ATP synthesis and ATP consumption, improving contractile performance following ischemia-reperfusion insult. Thus, the plasticity of phosphotransfer networks contributes to the effective functioning of the cellular energetic system, providing a mechanism for increased tolerance toward injury. Cell survival is critically dependent on the preservation of cellular bioenergetics. However, the metabolic mechanisms that confer resistance to injury are poorly understood. Phosphotransfer reactions integrate ATP-consuming with ATP-producing processes and could thereby contribute to the generation of a protective phenotype. Here, we used ischemic preconditioning to induce a stress-tolerant state and 18O-assisted31P nuclear magnetic resonance spectroscopy to capture intracellular phosphotransfer dynamics. Preconditioning of isolated perfused hearts triggered a redistribution in phosphotransfer flux with significant increase in creatine kinase and glycolytic rates. High energy phosphoryl fluxes through creatine kinase, adenylate kinase, and glycolysis in preconditioned hearts correlated tightly with post-ischemic functional recovery. This was associated with enhanced metabolite exchange between subcellular compartments, manifested by augmented transfer of inorganic phosphate from cellular ATPases to mitochondrial ATP synthase. Preconditioning-induced energetic remodeling protected cellular ATP synthesis and ATP consumption, improving contractile performance following ischemia-reperfusion insult. Thus, the plasticity of phosphotransfer networks contributes to the effective functioning of the cellular energetic system, providing a mechanism for increased tolerance toward injury. left ventricular end-diastolic pressure creatine phosphate glucose-6-phosphate Cells with high energy turnover are particularly vulnerable to insults induced by deprivation of oxygen and metabolic substrates (1Otterbein L.E. Bach F.H. Alam J. Soares M. Tao Lu H. Wysk M. Davis R.J. Flavell R.A. Choi A.M. Nat. Med. 2000; 6: 422-428Crossref PubMed Scopus (1808) Google Scholar, 2Lee J.M. Zipfel G.J. Choi D.W. Nature. 1999; 399: A7-A14Crossref PubMed Scopus (995) Google Scholar, 3Bolli R. Marban E. Physiol. Rev. 1999; 79: 609-634Crossref PubMed Scopus (858) Google Scholar). Recently, endogenous defense mechanisms have been discovered that can “precondition” cells to withstand metabolic stress (3Bolli R. Marban E. Physiol. Rev. 1999; 79: 609-634Crossref PubMed Scopus (858) Google Scholar, 4Jennings R.B. Steenbergen C. Reimer K.A. Monogr. Pathol. 1995; 37: 47-80PubMed Google Scholar). Preconditioning underlying cytoprotection has implicated multiple metabolic, signal transduction, and electrical events (3Bolli R. Marban E. Physiol. Rev. 1999; 79: 609-634Crossref PubMed Scopus (858) Google Scholar, 4Jennings R.B. Steenbergen C. Reimer K.A. Monogr. Pathol. 1995; 37: 47-80PubMed Google Scholar, 5Heurteaux C. Lauritzen I. Widmann C. Lazdunski M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4666-4670Crossref PubMed Scopus (540) Google Scholar, 6Morimoto R.I. Santoro M.G. Nat. Biotechnol. 1998; 16: 833-838Crossref PubMed Scopus (506) Google Scholar, 7Jovanovic N. Jovanovic S. Jovanovic A. Terzic A. FASEB J. 1999; 13: 923-929Crossref PubMed Scopus (54) Google Scholar, 8Cohen M.V. Baines C.P. Downey J.M. Annu. Rev. Physiol. 2000; 62: 79-109Crossref PubMed Scopus (448) Google Scholar, 9Gross G.J. Basic Res. Cardiol. 2000; 95: 280-284Crossref PubMed Scopus (81) Google Scholar, 10Terzic A. Dzeja P.P. Holmuhamedov E.L. J. Mol. Cell. Cardiol. 2000; 32: 1911-1915Abstract Full Text PDF PubMed Scopus (21) Google Scholar). However, the actual mechanisms responsible for preservation of cellular energetic systems and, ultimately, functional recovery remain poorly understood.In the heart, coupling of energetics with contractile function is facilitated through phosphotransfer relays, catalyzed by creatine kinase, adenylate kinase, and glycolysis (11Dzeja P.P. Vitkevicius K.T. Redfield M.M. Burnett J.C. Terzic A. Circ. Res. 1999; 84: 1137-1143Crossref PubMed Scopus (175) Google Scholar, 12Bessman S.P. Carpenter C.L. Annu. Rev. Biochem. 1985; 54: 831-862Crossref PubMed Scopus (582) Google Scholar, 13van Deursen J. Heerschap A. Oerlemans F. Ruitenbeek W. Jap P. ter Laak H. Wieringa B. Cell. 1993; 74: 621-631Abstract Full Text PDF PubMed Scopus (276) Google Scholar, 14Janssen E. Dzeja P.P. Oerlemans F. Simonetti A.W. Heerschap A. de Haan A. Rush P.S. Terjung R.R. Wieringa B. Terzic A. EMBO J. 2000; 19: 6371-6381Crossref PubMed Scopus (127) Google Scholar, 15Dzeja P.P. Terzic A. FASEB J. 1998; 12: 523-529Crossref PubMed Scopus (131) Google Scholar). Poor contractile performance in the failing myocardium is associated with deficits in phosphotransfer-dependent metabolic signaling (16Nascimben L. Ingwall J.C. Pauletto P. Friedrich J. Gwathmey J.K. Saks V. Pessina A.C. Allen P.D. Circulation. 1996; 94: 1894-1901Crossref PubMed Scopus (268) Google Scholar, 17De Sousa E. Veksler V. Minajeva A. Kaasik A. Mateo P. Mayoux E. Hoerter J. Bigard X. Serrurier B. Ventura-Clapier R. Circ. Res. 1999; 85: 68-76Crossref PubMed Scopus (127) Google Scholar, 18Dzeja P.P. Pucar D. Redfield M.M. Burnett J.C. Terzic A. Mol. Cell. Biochem. 1999; 201: 33-40Crossref PubMed Google Scholar, 19Shen W. Asai K. Uechi M. Mathier M.A. Shannon R.P. Vatner S.F. Ingwall J.S. Circulation. 2000; 100: 2113-2118Crossref Scopus (146) Google Scholar). Furthermore, disruption in phosphotransfer enzymes compromises the ability of heart muscle to respond to metabolic stress (20Ventura-Clapier R. Kuznetsov A.V. d'Albis A. van Deursen J. Wieringa B. Veksler V.I. J. Biol. Chem. 1995; 270: 19914-19920Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 21Saupe K.W. Spindler M. Tian R. Ingwall J.S. Circ. Res. 1998; 82: 898-907Crossref PubMed Scopus (159) Google Scholar, 22Pucar D. Janssen E. Dzeja P.P. Juranic N. Macura S. Wieringa B. Terzic A. J. Biol. Chem. 2000; 275: 41424-41429Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 23Saupe K.W. Spindler M. Hopkins J.C. Shen W. Ingwall J.S. J. Biol. Chem. 2000; 275: 19742-19746Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Alterations in cellular energy metabolism triggered by ischemic preconditioning, including a characteristic creatine phosphate overshoot, indicates that this protective process targets phosphotransfer reactions (24Jennings R.B. Reimer K.A. Annu. Rev. Med. 1991; 42: 225-246Crossref PubMed Scopus (262) Google Scholar, 25Takeo S. Nasa Y. Cardiovasc. Res. 1999; 43: 32-43Crossref PubMed Scopus (34) Google Scholar, 26Hassinen I.E. Vuorinen K.H. Ylitalo K. Ala-Rami A. Mol. Cell. Biochem. 1998; 184: 393-400Crossref PubMed Google Scholar, 27Garnier A. Rossi A. Lavanchy N. J. Mol. Cell. Cardiol. 1996; 28: 1671-1682Abstract Full Text PDF PubMed Scopus (22) Google Scholar). However, direct evidence demonstrating the protective role of phosphotransfer networks in the preconditioned state is still lacking.Here, we demonstrate that ischemic preconditioning of heart muscle induces remodeling in cellular energy transduction, transfer, and utilization processes, thereby promoting preservation of energy metabolism. Post-ischemic contractile recovery was tightly associated with preconditioning-induced adjustment in metabolic flux through creatine kinase, adenylate kinase, and glycolytic systems. Thus, preconditioning shifts intracellular phosphotransfer networks into a stress-tolerant mode rendering heart muscle more resistant to metabolic injury.DISCUSSIONInduction of the cytoprotective response is fundamental to cell survival under stress, and yet the mechanisms underlying acquired tolerance to metabolic injury are poorly understood. Here, we demonstrate by the novel approach of 18O/31P NMR analysis the importance of intracellular phosphotransfer pathways in producing a stress-tolerant cellular energetic phenotype. Preconditioning induced redistribution of high energy phosphoryl transfer through individual phosphotransfer reactions catalyzed by creatine kinase, adenylate kinase, and glycolytic enzymes, leading to an improved intracellular metabolic communication and preservation of cellular ATP synthesis and ATP consumption processes. Thus, the present study establishes that adaptive remodeling of the cellular energetic system is an integral mechanism in ischemic preconditioning-induced cell resistance to stress.The energetic homeostasis of the cell and, consequently, energy-driven cellular functions require tight coordination between ATP utilization and ATP generation (38Dzeja P.P. Redfield M.M. Burnett J.C. Terzic A. Curr. Cardiol. Rep. 2000; 2: 212-217Crossref PubMed Scopus (88) Google Scholar, 39Taegtmeyer H. Curr. Probl. Cardiol. 1994; 19: 59-113Crossref PubMed Scopus (331) Google Scholar, 40Hochachka P.W. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12233-12239Crossref PubMed Scopus (121) Google Scholar). Such coordination is believed to be mediated by phosphotransfer relays composed of creatine kinase, adenylate kinase, and glycolytic enzymes that facilitate high energy phosphoryl delivery and removal of ATPase end-products (12Bessman S.P. Carpenter C.L. Annu. Rev. Biochem. 1985; 54: 831-862Crossref PubMed Scopus (582) Google Scholar, 36Saks V.A. Tiivel T. Kay L. Novel-Chate V. Daneshrad Z. Rossi A. Fontaine E. Keriel C. Leverve X. Ventura-Clapier R. Anflous K. Samuel J.L. Rappaport L. Mol. Cell. Biochem. 1996; 160–161: 195-208Crossref PubMed Scopus (36) Google Scholar, 37Dzeja P.P. Zeleznikar R.J. Goldberg N.D. Mol. Cell. Biochem. 1998; 84: 169-182Crossref Google Scholar,41Tian R. Christe M.E. Spindler M. Hopkins J.C. Halow J.M. Camacho S.A. Ingwall J.S. J. Clin. Invest. 1997; 99: 745-751Crossref PubMed Scopus (89) Google Scholar). Here, phosphotransfer dynamics were dissected by18O/31P NMR spectroscopy, which allowed simultaneous capture of net phosphotransfer flux through individual enzymes, as well as total ATP production and consumption rates in intact heart muscle. In nonconditioned hearts, a prolonged ischemia-reperfusion challenge produced a marked reduction in the rates of creatine kinase, adenylate kinase, and glycolysis-catalyzed phosphotransfer, contributing to energetic and contractile dysfunction of the post-ischemic myocardium. Phosphotransfer deficit further disrupted intracellular handling of Pi, resulting in the accumulation of nascent Pi at ATPase sites and impaired delivery to mitochondrial ATP synthase. A restricted mobility of intracellular Pi could be the result of functional entrapment and/or physical diffusional restriction due to the viscosity and high structural organization of the muscle cytosol (15Dzeja P.P. Terzic A. FASEB J. 1998; 12: 523-529Crossref PubMed Scopus (131) Google Scholar, 18Dzeja P.P. Pucar D. Redfield M.M. Burnett J.C. Terzic A. Mol. Cell. Biochem. 1999; 201: 33-40Crossref PubMed Google Scholar). This would negatively impact ATPase activity responsible for efficient contraction-relaxation cycles and contribute to reduced ATP synthesis by oxidative phosphorylation (41Tian R. Christe M.E. Spindler M. Hopkins J.C. Halow J.M. Camacho S.A. Ingwall J.S. J. Clin. Invest. 1997; 99: 745-751Crossref PubMed Scopus (89) Google Scholar). With short-term hypoxia, the drop in creatine kinase flux is usually compensated for by increased adenylate kinase and/or glycolytic flux (22Pucar D. Janssen E. Dzeja P.P. Juranic N. Macura S. Wieringa B. Terzic A. J. Biol. Chem. 2000; 275: 41424-41429Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 37Dzeja P.P. Zeleznikar R.J. Goldberg N.D. Mol. Cell. Biochem. 1998; 84: 169-182Crossref Google Scholar, 42Carrasco A.J. Dzeja P.P. Alekseev A.E. Pucar D. Zingman L.V. Abraham M.R. Hodgson D. Bienengraeber M. Puceat M. Janssen E. Wieringa B. Terzic A. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 7623-7628Crossref PubMed Scopus (216) Google Scholar). However, with prolonged metabolic stress, uncompensated deficits in phosphotransfer enzymes do develop, as observed here and as previously reported in severe cardiac conditions such as heart failure and various forms of myocardial insufficiency (11Dzeja P.P. Vitkevicius K.T. Redfield M.M. Burnett J.C. Terzic A. Circ. Res. 1999; 84: 1137-1143Crossref PubMed Scopus (175) Google Scholar, 16Nascimben L. Ingwall J.C. Pauletto P. Friedrich J. Gwathmey J.K. Saks V. Pessina A.C. Allen P.D. Circulation. 1996; 94: 1894-1901Crossref PubMed Scopus (268) Google Scholar, 17De Sousa E. Veksler V. Minajeva A. Kaasik A. Mateo P. Mayoux E. Hoerter J. Bigard X. Serrurier B. Ventura-Clapier R. Circ. Res. 1999; 85: 68-76Crossref PubMed Scopus (127) Google Scholar, 18Dzeja P.P. Pucar D. Redfield M.M. Burnett J.C. Terzic A. Mol. Cell. Biochem. 1999; 201: 33-40Crossref PubMed Google Scholar, 19Shen W. Asai K. Uechi M. Mathier M.A. Shannon R.P. Vatner S.F. Ingwall J.S. Circulation. 2000; 100: 2113-2118Crossref Scopus (146) Google Scholar). The deletion of genes encoding creatine kinase or adenylate kinase compromises the ability of a muscle to sustain cellular energetic economy under metabolic stress (14Janssen E. Dzeja P.P. Oerlemans F. Simonetti A.W. Heerschap A. de Haan A. Rush P.S. Terjung R.R. Wieringa B. Terzic A. EMBO J. 2000; 19: 6371-6381Crossref PubMed Scopus (127) Google Scholar, 20Ventura-Clapier R. Kuznetsov A.V. d'Albis A. van Deursen J. Wieringa B. Veksler V.I. J. Biol. Chem. 1995; 270: 19914-19920Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 21Saupe K.W. Spindler M. Tian R. Ingwall J.S. Circ. Res. 1998; 82: 898-907Crossref PubMed Scopus (159) Google Scholar, 22Pucar D. Janssen E. Dzeja P.P. Juranic N. Macura S. Wieringa B. Terzic A. J. Biol. Chem. 2000; 275: 41424-41429Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 23Saupe K.W. Spindler M. Hopkins J.C. Shen W. Ingwall J.S. J. Biol. Chem. 2000; 275: 19742-19746Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar,43Steeghs K. Benders A. Oerlemans F. de Haan A. Heerschap A. Ruitenbeek W. Jost C. van Deursen J. Perryman B. Pette D. Bruckwilder M. Koudijs J. Jap P. Veerkamp J. Wieringa B. Cell. 1997; 89: 93-103Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Thus, defective phosphotransfer networking, associated with a reduced rate of ATP turnover, precipitates poor myocardial recovery in the nonconditioned myocardium following ischemia-reperfusion.Preconditioning improves myocardial post-ischemic contractile recovery and provides protection from metabolic injury (4Jennings R.B. Steenbergen C. Reimer K.A. Monogr. Pathol. 1995; 37: 47-80PubMed Google Scholar, 8Cohen M.V. Baines C.P. Downey J.M. Annu. Rev. Physiol. 2000; 62: 79-109Crossref PubMed Scopus (448) Google Scholar, 9Gross G.J. Basic Res. Cardiol. 2000; 95: 280-284Crossref PubMed Scopus (81) Google Scholar, 24Jennings R.B. Reimer K.A. Annu. Rev. Med. 1991; 42: 225-246Crossref PubMed Scopus (262) Google Scholar). In the present study, by 18O/31P NMR analysis of myocardial phosphotransfer dynamics we found that preconditioning up-regulates creatine kinase phosphotransfer flux associated with higher levels of CrP and an improved CrP/Piratio. This finding supports the notion that preconditioning-induced creatine phosphate overshoot is required for generation of the protective phenotype (24Jennings R.B. Reimer K.A. Annu. Rev. Med. 1991; 42: 225-246Crossref PubMed Scopus (262) Google Scholar, 25Takeo S. Nasa Y. Cardiovasc. Res. 1999; 43: 32-43Crossref PubMed Scopus (34) Google Scholar, 26Hassinen I.E. Vuorinen K.H. Ylitalo K. Ala-Rami A. Mol. Cell. Biochem. 1998; 184: 393-400Crossref PubMed Google Scholar, 27Garnier A. Rossi A. Lavanchy N. J. Mol. Cell. Cardiol. 1996; 28: 1671-1682Abstract Full Text PDF PubMed Scopus (22) Google Scholar, 44Forbes R.A. Steenbergen C. Murphy E. Circ. Res. 2001; 88: 802-809Crossref PubMed Scopus (352) Google Scholar). In addition to the creatine kinase system, preconditioning also markedly increased glycolytic phosphotransfer associated with higher lactate and α-glycerophosphate levels. Previous studies have indicated increased glucose utilization and reduced glycogenolysis in preconditioning, leading to maintained glycolytic flux at reperfusion (25Takeo S. Nasa Y. Cardiovasc. Res. 1999; 43: 32-43Crossref PubMed Scopus (34) Google Scholar, 45Weiss R.G. de Albuquerque C.P. Vandegaer K. Chacko V.P. Gerstenblith G. Circ. Res. 1996; 79: 435-446Crossref PubMed Scopus (53) Google Scholar, 46Janier M.F. Vanoverschelde J.L. Bergmann S.R. Am. J. Physiol. 1994; 267: H1353-H1360PubMed Google Scholar). Traditionally, glycolytic metabolism has been identified as an alternative source of myocardial ATP production. The present finding supports an additional role for glycolysis in transferring and distributing high energy phosphoryls in line with vigorous phosphoryl exchange rates in the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase system observed with31P NMR saturation transfer (47Sako E.Y. Kingsley-Hickman P.B. From A.H. Foker J.E. Ugurbil K. J. Biol. Chem. 1988; 263: 10600-10607Abstract Full Text PDF PubMed Google Scholar, 48Kingsley-Hickman P.B. Sako E.Y. Mohanakrishnan P. Robitaille P.M. From A.H. Foker J.E. Ugurbil K. Biochemistry. 1987; 26: 7501-7510Crossref PubMed Scopus (104) Google Scholar). In fact, increased phosphotransfer in the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate couple could be responsible for improved intracellular Pi trafficking (15Dzeja P.P. Terzic A. FASEB J. 1998; 12: 523-529Crossref PubMed Scopus (131) Google Scholar, 18Dzeja P.P. Pucar D. Redfield M.M. Burnett J.C. Terzic A. Mol. Cell. Biochem. 1999; 201: 33-40Crossref PubMed Google Scholar) observed in preconditioning hearts. In contrast to the increased contribution of creatine kinase and glycolytic flux, adenylate kinase phosphotransfer in the preconditioned myocardium showed an apparent trend toward down-regulation. This finding may suggest increased competition with creatine kinase and glycolytic systems leading to redistribution of intracellular phosphotransfer flux. Thus, in the preconditioned mode, cellular phosphotransfer equilibrium would operate at a new steady state conditioning cells to withstand subsequent metabolic stress.The remodeling of cellular metabolism has been considered as a contributor to metabolic defense (22Pucar D. Janssen E. Dzeja P.P. Juranic N. Macura S. Wieringa B. Terzic A. J. Biol. Chem. 2000; 275: 41424-41429Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 27Garnier A. Rossi A. Lavanchy N. J. Mol. Cell. Cardiol. 1996; 28: 1671-1682Abstract Full Text PDF PubMed Scopus (22) Google Scholar, 40Hochachka P.W. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12233-12239Crossref PubMed Scopus (121) Google Scholar). Apparently, the plasticity of cellular energetic dynamics materializes in a more efficient coupling of ATP turnover with cellular functions. Tight correlation was discovered here between metabolic fluxes through creatine kinase, adenylate kinase, and glycolytic phosphotransfer and contractile recovery of post-ischemic hearts. The close correlation between phosphotransfer flux and heart muscle performance in the post-ischemic state suggests that phosphotransfer reactions are an obligatory route channeling the flow of high energy phosphoryls. Thus, integrated cellular energetics contributes to the preconditioned phenotype by translating metabolic adaptation into increased stress tolerance.The sequences of events leading to the development of a preconditioning state are still not fully understood. However, a number of signal transduction cascades, including protein kinases and ion channels, have been implicated as triggers and/or effectors of the protective phenotype (4Jennings R.B. Steenbergen C. Reimer K.A. Monogr. Pathol. 1995; 37: 47-80PubMed Google Scholar, 8Cohen M.V. Baines C.P. Downey J.M. Annu. Rev. Physiol. 2000; 62: 79-109Crossref PubMed Scopus (448) Google Scholar, 9Gross G.J. Basic Res. Cardiol. 2000; 95: 280-284Crossref PubMed Scopus (81) Google Scholar, 10Terzic A. Dzeja P.P. Holmuhamedov E.L. J. Mol. Cell. Cardiol. 2000; 32: 1911-1915Abstract Full Text PDF PubMed Scopus (21) Google Scholar). Rapid alterations in cellular energetics induced by ischemic preconditioning could trigger signal transduction events by changing the cellular phosphorylation potential. Indeed, there is a close relationship between creatine kinase phosphotransfer and the activity of protein kinase C, believed to be critical in early stages of preconditioning (49Wallimann T. Wyss M. Brdiczka D. Nicolay K. Eppenberger H.M. Biochem. J. 1992; 281: 21-40Crossref PubMed Scopus (1583) Google Scholar). Moreover, adenylate kinase phosphotransfer, through AMP-driven signaling, modulates the behavior of the AMP-activated protein kinase, a metabolic stress kinase (50Hardie D.G. Salt I.P. Hawley S.A. Davies S.P. Biochem. J. 1999; 338: 717-722Crossref PubMed Scopus (315) Google Scholar). Furthermore, intracellular phosphotransfer reactions regulate the behavior of ATP-sensitive K+ (KATP) channels, an alarm mechanism setting membrane excitability in response to metabolic stress (15Dzeja P.P. Terzic A. FASEB J. 1998; 12: 523-529Crossref PubMed Scopus (131) Google Scholar, 42Carrasco A.J. Dzeja P.P. Alekseev A.E. Pucar D. Zingman L.V. Abraham M.R. Hodgson D. Bienengraeber M. Puceat M. Janssen E. Wieringa B. Terzic A. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 7623-7628Crossref PubMed Scopus (216) Google Scholar, 51Elvir-Mairena J.R. Jovanovic A. Gomez L.A. Alekseev A.E. Terzic A. J. Biol. Chem. 1996; 271: 31903-31908Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 52Jovanovic A. Jovanovic S. Lorenz E. Terzic A. Circulation. 1998; 98: 1548-1555Crossref PubMed Scopus (112) Google Scholar, 53Terzic A. Clin. Pharmacol. Ther. 1999; 66: 105-109Crossref PubMed Google Scholar, 54Bienengraeber M. Alekseev A.E. Abraham M.R. Carrasco A.J. Moreau C. Vivaudou M. Dzeja P.P. Terzic A. FASEB J. 2000; 14: 1943-1952Crossref PubMed Scopus (124) Google Scholar, 55Zingman L.V. Alekseev A.E. Bienengraeber M. Hodgson D. Karger A.B. Dzeja P.P. Terzic A. Neuron. 2001; 31: 233-245Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar). In turn, both protein kinase C and AMP-activated protein kinase regulate creatine kinase phosphotransfer rate and other metabolic pathways through phosphorylation of target proteins (49Wallimann T. Wyss M. Brdiczka D. Nicolay K. Eppenberger H.M. Biochem. J. 1992; 281: 21-40Crossref PubMed Scopus (1583) Google Scholar, 56Ponticos M. Lu Q.L. Morgan J.E. Hardie D.G. Partridge T.A. Carling D. EMBO J. 1998; 17: 1688-1699Crossref PubMed Scopus (274) Google Scholar). Thus, the feedback communication between stress-sensitive metabolic and signal transduction events may be central to the generation of the preconditioned state.In summary, this study has uncovered a homeostatic mechanism by which cells induce a preconditioned energetic state conferring increased tolerance toward injury. This is accomplished by a coordinated redistribution of high energy phosphoryl flux through phosphotransfer enzymes allowing more efficient communication of energetic signals and preservation of ATP generation and consumption processes. In this way, intracellular phosphotransfer reactions emerge as an essential component required for the development of an injury-tolerant state and could thereby serve as a target for regulating the cellular response to stress. Cells with high energy turnover are particularly vulnerable to insults induced by deprivation of oxygen and metabolic substrates (1Otterbein L.E. Bach F.H. Alam J. Soares M. Tao Lu H. Wysk M. Davis R.J. Flavell R.A. Choi A.M. Nat. Med. 2000; 6: 422-428Crossref PubMed Scopus (1808) Google Scholar, 2Lee J.M. Zipfel G.J. Choi D.W. Nature. 1999; 399: A7-A14Crossref PubMed Scopus (995) Google Scholar, 3Bolli R. Marban E. Physiol. Rev. 1999; 79: 609-634Crossref PubMed Scopus (858) Google Scholar). Recently, endogenous defense mechanisms have been discovered that can “precondition” cells to withstand metabolic stress (3Bolli R. Marban E. Physiol. Rev. 1999; 79: 609-634Crossref PubMed Scopus (858) Google Scholar, 4Jennings R.B. Steenbergen C. Reimer K.A. Monogr. Pathol. 1995; 37: 47-80PubMed Google Scholar). Preconditioning underlying cytoprotection has implicated multiple metabolic, signal transduction, and electrical events (3Bolli R. Marban E. Physiol. Rev. 1999; 79: 609-634Crossref PubMed Scopus (858) Google Scholar, 4Jennings R.B. Steenbergen C. Reimer K.A. Monogr. Pathol. 1995; 37: 47-80PubMed Google Scholar, 5Heurteaux C. Lauritzen I. Widmann C. Lazdunski M. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4666-4670Crossref PubMed Scopus (540) Google Scholar, 6Morimoto R.I. Santoro M.G. Nat. Biotechnol. 1998; 16: 833-838Crossref PubMed Scopus (506) Google Scholar, 7Jovanovic N. Jovanovic S. Jovanovic A. Terzic A. FASEB J. 1999; 13: 923-929Crossref PubMed Scopus (54) Google Scholar, 8Cohen M.V. Baines C.P. Downey J.M. Annu. Rev. Physiol. 2000; 62: 79-109Crossref PubMed Scopus (448) Google Scholar, 9Gross G.J. Basic Res. Cardiol. 2000; 95: 280-284Crossref PubMed Scopus (81) Google Scholar, 10Terzic A. Dzeja P.P. Holmuhamedov E.L. J. Mol. Cell. Cardiol. 2000; 32: 1911-1915Abstract Full Text PDF PubMed Scopus (21) Google Scholar). However, the actual mechanisms responsible for preservation of cellular energetic systems and, ultimately, functional recovery remain poorly understood. In the heart, coupling of energetics with contractile function is facilitated through phosphotransfer relays, catalyzed by creatine kinase, adenylate kinase, and glycolysis (11Dzeja P.P. Vitkevicius K.T. Redfield M.M. Burnett J.C. Terzic A. Circ. Res. 1999; 84: 1137-1143Crossref PubMed Scopus (175) Google Scholar, 12Bessman S.P. Carpenter C.L. Annu. Rev. Biochem. 1985; 54: 831-862Crossref PubMed Scopus (582) Google Scholar, 13van Deursen J. Heerschap A. Oerlemans F. Ruitenbeek W. Jap P. ter Laak H. Wieringa B. Cell. 1993; 74: 621-631Abstract Full Text PDF PubMed Scopus (276) Google Scholar, 14Janssen E. Dzeja P.P. Oerlemans F. Simonetti A.W. Heerschap A. de Haan A. Rush P.S. Terjung R.R. Wieringa B. Terzic A. EMBO J. 2000; 19: 6371-6381Crossref PubMed Scopus (127) Google Scholar, 15Dzeja P.P. Terzic A. FASEB J. 1998; 12: 523-529Crossref PubMed Scopus (131) Google Scholar). Poor contractile performance in the failing myocardium is associated with deficits in phosphotransfer-dependent metabolic signaling (16Nascimben L. Ingwall J.C. Pauletto P. Friedrich J. Gwathmey J.K. Saks V. Pessina A.C. Allen P.D. Circulation. 1996; 94: 1894-1901Crossref PubMed Scopus (268) Google Scholar, 17De Sousa E. Veksler V. Minajeva A. Kaasik A. Mateo P. Mayoux E. Hoerter J. Bigard X. Serrurier B. Ventura-Clapier R. Circ. 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Here, we demonstrate that ischemic preconditioning of heart muscle induces remodeling in cellular ener" @default.
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