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2004 | 51 | 2 | 379-390
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Role of the mitochondrial ATP-sensitive K+ channels in cardioprotection.

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The mitochondrial ATP-sensitive K+ (mitoKATP) channel was discovered more than a decade ago. Since then, several pharmacological studies have identified agents that target this channel some of which selectively target mitoKATP. These and other studies have also suggested that mitoKATP plays a key role in the process of ischemic preconditioning (IPC) and prevention of apoptosis. The mechanism by which mitoKATP exerts its protective effects is unclear, however, changes in mitochondrial Ca2+ uptake and levels of reactive oxygen species, and mitochondrial matrix swelling are believed to be involved. Despite major advances, several important issues regarding mitoKATP remain unanswered. These questions include, but are not limited to: the molecular structure of mitoKATP, the downstream and upstream mechanisms that leads to IPC and cell death, and the pharmacological profile of the channel. This review attempts to provide an up-to-date overview of the role of mitoKATP in cardioprotection.
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  • ivision of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, U.S.A.
  • Aguilar-Bryan L, Nichols CG, Wechsler SW, Clement JPt, Boyd AE 3rd, Gonzalez G, Herrera-Sosa H, Nguy K, Bryan J, Nelson DA. (1995) Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science.; 268: 423-6.
  • Akao M, Ohler A, O'Rourke B, Marban E. (2001) Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. Circ Res.; 88: 1267-75.
  • Ardehali H, Chen Z, Ko Y, Mejia-Alvarez R, Marban E. (2003) Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. Circulation.; 108 (suppl I): I-1004.
  • Bajgar R, Seetharaman S, Kowaltowski AJ, Garlid KD, Paucek P. (2001) Identification and properties of a novel intracellular (mitochondrial) ATP-sensitive potassium channel in brain. J Biol Chem.; 276: 33369-74.
  • Brierley GP, Jurkowitz M, Chavez E, Jung DW. (1977) Energy-dependent contraction of swollen heart mitochondria. J Biol Chem.; 252: 7932-9.
  • Chance B. (1972) The kinetics of flavoprotein and pyridine nucleotide oxidation in cardiac mitochondria in the presence of calcium. FEBS Lett.; 26: 315-9.
  • Chance B, Salkovitz IA, Kovach AG. (1972) Kinetics of mitochondrial flavoprotein and pyridine nucleotide in perfused heart. Am J Physiol.; 223: 207-18.
  • Cohen MV, Baines CP, Downey JM. (2000) Ischemic preconditioning: from adenosine receptor to K(ATP) channel. Annu Rev Physiol.; 62: 79-109.
  • Debska G, Kicinska A, Skalska J, Szewczyk A, May R, Elger CE, Kunz WS. (2002) Opening of potassium channels modulates mitochondrial function in rat skeletal muscle. Biochim Biophys Acta.; 1556: 97-105.
  • Forbes RA, Steenbergen C, Murphy E. (2001) Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res.; 88: 802-9.
  • Fryer RM, Hsu AK, Eells JT, Nagase H, Gross GJ. (1999) Opioid-induced second window of cardioprotection: potential role of mitochondrial KATP channels. Circ Res.; 84: 846-51.
  • Garlid KD, Beavis AD. (1986) Evidence for the existence of an inner membrane anion channel in mitochondria. Biochim Biophys Acta.; 853: 187-204.
  • Garlid KD, Paucek P. (2001) The mitochondrial potassium cycle. IUBMB Life.; 52: 153-8.
  • Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D'Alonzo AJ, Lodge NJ, Smith MA, Grover GJ. (1997) Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res.; 81: 1072-82.
  • Grigoriev SM, Skarga YY, Mironova GD, Marinov BS. (1999) Regulation of mitochondrial KATP channel by redox agents. Biochim Biophys Acta.; 1410: 91-6.
  • Gross GJ, Fryer RM. (1999) Sarcolemmal versus mitochondrial ATP-sensitive K+ channels and myocardial preconditioning. Circ Res.; 84: 973-9.
  • Grover GJ, Garlid KD. (2000) ATP-Sensitive potassium channels: a review of their cardioprotective pharmacology. J Mol Cell Cardiol.; 32: 677-95.
  • Grover GJ, D'Alonzo AJ, Dzwonczyk S, Parham CS, Darbenzio RB. (1996) Preconditioning is not abolished by the delayed rectifier K+ blocker dofetilide. Am J Physiol.; 271: H1207-14.
  • Halestrap AP. (1989) The regulation of the matrix volume of mammalian mitochondria in vivo and in vitro and its role in the control of mitochondrial metabolism. Biochim Biophys Acta.; 973: 355-82.
  • Hanley PJ, Mickel M, Loffler M, Brandt U, Daut J. (2002) K(ATP) channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart. J Physiol.; 542: 735-41.
  • Hassinen I, Chance B. (1968) Oxidation-reduction properties of the mitochondrial flavoprotein chain. Biochem Biophys Res Commun.; 31: 895-900.
  • Holmuhamedov EL, Wang L, Terzic A. (1999) ATP-sensitive K+ channel openers prevent Ca2+ overload in rat cardiac mitochondria. J Physiol (Lond).; 519 (Pt 2): 347-60.
  • Horiguchi T, Kis B, Rajapakse N, Shimizu K, Busija DW. (2003) Opening of mitochondrial ATP-sensitive potassium channels is a trigger of 3-nitropropionic acid-induced tolerance to transient focal cerebral ischemia in rats. Stroke.; 34: 1015-20.
  • Hu H, Sato T, Seharaseyon J, Liu Y, Johns DC, O'Rourke B, Marban E. (1999) Pharmacological and histochemical distinctions between molecularly defined sarcolemmal KATP channels and native cardiac mitochondrial KATP channels. Mol Pharmacol.; 55: 1000-5.
  • Inagaki N, Gonoi T, Clement JPt, Namba N, Inazawa J, Gonzalez G, Aguilar-Bryan L, Seino S, Bryan J. (1995a) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science.; 270: 1166-70.
  • Inagaki N, Tsuura Y, Namba N, Masuda K, Gonoi T, Horie M, Seino Y, Mizuta M, Seino S. (1995b) Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues including pancreatic islets pituitary skeletal muscle and heart. J Biol Chem.; 270: 5691-4.
  • Inagaki N, Gonoi T, Clement JP, Wang CZ, Aguilar-Bryan L, Bryan J, Seino S. (1996) A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron.; 16: 1011-7.
  • Inoue I, Nagase H, Kishi K, Higuti T. (1991) ATP-sensitive K+ channel in the mitochondrial inner membrane. Nature.; 352: 244-7.
  • Jaburek M, Yarov-Yarovoy V, Paucek P, Garlid KD. (1998) State-dependent inhibition of the mitochondrial KATP channel by glyburide and 5-hydroxydecanoate. J Biol Chem.; 273: 13578-82.
  • Jezek P, Orosz DE, Garlid KD. (1990) Reconstitution of the uncoupling protein of brown adipose tissue mitochondria. Demonstration of GDP-sensitive halide anion uniport. J Biol Chem.; 265: 19296-302.
  • Kloner RA, Bolli R, Marban E, Reinlib L, Braunwald E. (1998) Medical and cellular implications of stunning hibernation, and preconditioning: an NHLBI workshop. Circulation.; 97: 1848-67.
  • Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. (2001) Bioenergetic consequences of opening the ATP-sensitive K+ channel of heart mitochondria. Am J Physiol Heart Circ Physiol.; 280: H649-57.
  • Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M. (1993) Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res.; 72: 1293-9.
  • Lacza Z, Snipes JA, Kis B, Szabo C, Grover G, Busija DW. (2003a) Investigation of the subunit composition and the pharmacology of the mitochondrial ATP-dependent K+ channel in the brain. Brain Res.; 994: 27-36.
  • Lacza Z, Snipes JA, Miller AW, Szabo C, Grover G, Busija DW. (2003b) Heart mitochondria contain functional ATP-dependent K+ channels. J Mol Cell Cardiol.; 35: 1339-47.
  • Lim KH, Javadov SA, Das M, Clarke SJ, Suleiman MS, Halestrap AP. (2002) The effects of ischaemic preconditioning diazoxide and 5-hydroxydecanoate on rat heart mitochondrial volume and respiration. J Physiol.; 545: 961-74.
  • Liu Y, Sato T, O'Rourke B, Marban E. (1998) Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? Circulation.; 97: 2463-9.
  • Marber MS, Latchman DS, Walker JM, Yellon DM. (1993) Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation.; 88: 1264-72.
  • Marinov BS, Grigoriev SM, Skarga Y, Olovjanishnikova GD, Mironova GD. (2001) Effects of pelargonidine and a benzocaine analogue p-diethylaminoethyl benzoate on mitochondrial K(ATP) channel. Membr Cell Biol.; 14: 663-71.
  • McCully JD, Levitsky S. (2003) The mitochondrial K(ATP) channel and cardioprotection. Ann Thorac Surg.; 75: S667-73.
  • Mei DA, Elliott GT, Gross GJ. (1996) KATP channels mediate late preconditioning against infarction produced by monophosphoryl lipid A. Am J Physiol.; 271: H2723-9.
  • Miki T, Suzuki M, Shibasaki T, Uemura H, Sato T, Yamaguchi K, Koseki H, Iwanaga T, Nakaya H, Seino S. (2002) Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nat Med.; 8: 466-72.
  • Minners J, van den Bos EJ, Yellon DM, Schwalb H, Opie LH, Sack MN. (2000) Dinitrophenol cyclosporin A and trimetazidine modulate preconditioning in the isolated rat heart: support for a mitochondrial role in cardioprotection. Cardiovasc Res.; 47: 68-73.
  • Mironova GD, Skarga YY, Grigoriev SM, Negoda AE, Kolomytkin OV, Marinov BS. (1999) Reconstitution of the mitochondrial ATP-dependent potassium channel into bilayer lipid membrane. J Bioenerg Biomembr.; 31: 159-63.
  • Murata M, Akao M, O'Rourke B, Marban E. (2001) Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca2+ overload during simulated ischemia and reperfusion: possible mechanism of cardioprotection. Circ Res.; 89: 891-8.
  • Murry CE, Jennings RB, Reimer KA. (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation.; 74: 1124-36.
  • Noma A. (1983) ATP-regulated K+ channels in cardiac muscle. Nature.; 305: 147-8.
  • Ockaili RA, Bhargava P, Kukreja RC. (2001) Chemical preconditioning with 3-nitropropionic acid in hearts: role of mitochondrial K(ATP) channel. Am J Physiol Heart Circ Physiol.; 280: H2406-11.
  • Oldenburg O, Cohen MV, Yellon DM, Downey JM. (2002) Mitochondrial K(ATP) channels: role in cardioprotection. Cardiovasc Res.; 55: 429-37.
  • O'Rourke B. (2000) Myocardial K(ATP) channels in preconditioning. Circ Res.; 87: 845-55.
  • O'Rourke B. (2004) Evidence for mitochondrial K+ channels and their role in cardioprotection. Circ Res.; 94: 420-32.
  • Ozcan C, Bienengraeber M, Dzeja PP, Terzic A. (2002) Potassium channel openers protect cardiac mitochondria by attenuating oxidant stress at reoxygenation. Am J Physiol Heart Circ Physiol.; 282: H531-9.
  • Pain T, Yang XM, Critz SD, Yue Y, Nakano A, Liu GS, Heusch G, Cohen MV, Downey JM. (2000) Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res.; 87: 460-6.
  • Paucek P, Mironova G, Mahdi F, Beavis AD, Woldegiorgis G, Garlid KD. (1992) Reconstitution and partial purification of the glibenclamide-sensitive ATP-dependent K+ channel from rat liver and beef heart mitochondria. J Biol Chem.; 267: 26062-9.
  • Sasaki N, Sato T, Ohler A, O'Rourke B, Marban E. (2000) Activation of mitochondrial ATP-dependent potassium channels by nitric oxide. Circulation.; 101: 439-45.
  • Sasaki N, Murata M, Guo Y, Jo SH, Ohler A, Akao M, O'Rourke B, Xiao RP, Bolli R, Marban E. (2003) MCC-134 a single pharmacophore opens surface ATP-sensitive potassium channels blocks mitochondrial ATP-sensitive potassium channels and suppresses preconditioning. Circulation.; 107: 1183-8.
  • Sato T, O'Rourke B, Marban E. (1998) Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res.; 83: 110-4.
  • Sato T, Sasaki N, O'Rourke B, Marban E. (2000a) Adenosine primes the opening of mitochondrial ATP-sensitive potassium channels: a key step in ischemic preconditioning? Circulation.; 102: 800-5.
  • Sato T, Sasaki N, Seharaseyon J, O'Rourke B, Marban E. (2000b) Selective pharmacological agents implicate mitochondrial but not sarcolemmal K(ATP) channels in ischemic cardioprotection. Circulation.; 101: 2418-23.
  • Seharaseyon J, Ohler A, Sasaki N, Fraser H, Sato T, Johns DC, O'Rourke B, Marban E. (2000a) Molecular composition of mitochondrial ATP-sensitive potassium channels probed by viral Kir gene transfer. J Mol Cell Cardiol.; 32: 1923-30.
  • Seharaseyon J, Sasaki N, Ohler A, Sato T, Fraser H, Johns DC, O'Rourke B, Marban E. (2000b) Evidence against functional heteromultimerization of the KATP channel subunits Kir6.1 and Kir6.2. J Biol Chem.; 275: 17561-5.
  • Suzuki M, Kotake K, Fujikura K, Inagaki N, Suzuki T, Gonoi T, Seino S, Takata K. (1997) Kir6.1: a possible subunit of ATP-sensitive K+ channels in mitochondria. Biochem Biophys Res Commun.; 241: 693-7.
  • Szewczyk A, Mikolajek B, Pikula S, Nalecz MJ. (1993) Potassium channel openers induce mitochondrial matrix volume changes via activation of ATP-sensitive K+ channel. Pol J Pharmacol.; 45: 437-43.
  • Takashi E, Wang Y, Ashraf M. (1999) Activation of mitochondrial K(ATP) channel elicits late preconditioning against myocardial infarction via protein kinase C signaling pathway [see comments]. Circ Res.; 85: 1146-53.
  • Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT. (1998) Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem.; 273: 18092-8.
  • Vanden Hoek TL, Becker LB, Shao ZH, Li CQ, Schumacker PT. (2000) Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res.; 86: 541-8.
  • Wang L, Cherednichenko G, Hernandez L, Halow J, Camacho SA, Figueredo V, Schaefer S. (2001) Preconditioning limits mitochondrial Ca2+ during ischemia in rat hearts: role of K(ATP) channels. Am J Physiol Heart Circ Physiol.; 280: H2321-8.
  • Weiss JN, Korge P, Honda HM, Ping P. (2003) Role of the mitochondrial permeability transition in myocardial disease. Circ Res.; 93: 292-301.
  • Yao Z, Gross GJ. (1994) Effects of the KATP channel opener bimakalim on coronary blood flow monophasic action potential duration and infarct size in dogs. Circulation.; 89: 1769-75.
  • Zhang DX, Chen YF, Campbell WB, Zou AP, Gross GJ, Li PL. (2001) Characteristics and superoxide-induced activation of reconstituted myocardial mitochondrial ATP-sensitive potassium channels. Circ Res.; 89: 1177-83.
  • Zweier JL, Flaherty JT, Weisfeldt ML. (1987) Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci U S A.; 84: 1404-7
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