Abstract
It has been recognized that eucaryotic cells respond to different external stimuli by activation of mechanisms of cell signaling. One of the major systems participating in the transduction of signal from the cell membrane to nuclear and other intracellular targets is the highly conserved mitogen-activated protein kinase (MAPK) superfamily. The members of MAPK family are involved in the regulation of a large variety of cellular processes, such as cell growth, differentiation, development, cell cycle, death, and survival. Several MAPK subfamilies, each with apparently unique signaling pathway, have been identified in the mammalian myocardium. These cascades differ in their upstream activation sequence and in downstream substrate specificity. Each pathway follows the same conserved three-kinase module consisting of MAPK, MAPK kinase (MKK or MEK), and MAPK kinase kinase. The major groups of MAPKs found in cardiac tissue include the extracellular signal-regulated kinases (ERKs), the stress-activated/c-Jun NH2-terminal kinases (SAPK/JNKs), p38-MAPK, and ERK5/big MAPK 1 (BMK1). The ERKs are strongly activated by mitogenic and growth factors and by physical stress, SAPK/JNKs and p38-MAPK can be activated by various cell stresses, such as hyperosmotic shock, metabolic stress, or protein synthesis inhibitors, ultraviolet radiation, heat shock, cytokines, and ischemia. Recently it has been proposed that activation of MAPK family and their downstream effectors plays a key role in the pathogenesis of various deleterious processes in the heart, for example, myocardial hypertrophy and its transition to heart failure, in ischemic and reperfusion injury, as well in the cardioprotection induced by ischemic preconditioning or pharmacologically.
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Chien, K. R., Knowlton, K. U., Zhu, H., and Chien, S. (1991) Regulation of cardiac gene expression during myocardial growth and hypertrophy: Molecular studies of an adaptive physiologic response. FASEB J. 5, 3037–3046.
Clerk, A., Fuller, S. J., Michael, A., and Sugden, P. H. (1998) Stimulation of “stress-regulated” mitogen-activated protein kinases (stress-activated protein kinases/c-Jun N-terminal kinases and p38-mitogen-activated protein kinases) in perfused rat hearts by oxidative and other stresses. J. Biol. Chem. 273, 7228–7334.
Talmor, D., Applebaum, A., Rudich, A., Shapira, Y., and Tirosh, A._(2000) Activation of mitogen-activated protein kinases in human heart during cardiopulmonary bypass. Circ. Res. 86, 1004–1007.
Sanada, S., Kitakaze, M., Papst, P. J., Hatanaka, K., Asanuma, H., Aki, T., et al. (2001) Role of phasic dynamism of p38 mitogen-activated protein kinase activation in ischemic preconditioning of the canine heart. Circ. Res. 88, 175–180.
Ping, P., Zhang, J., Huang, S., Cao, X., Tang, X. L., Li, R. C., et al. (1999) PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits. Am. J. Physiol. Heart Circ. Physiol. 277, H1771–1785.
Strohm, C., Barancik, M., Bruehl, M. L., Kilian, S. A. R., and Schaper, W. (2000) Inhibition of the ER-Kinase by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium. J. Cardiovasc. Pharmacol. 36, 218–229.
Tekin, D., Xi, L., Zhao, T., Tejero-Taldo, M. I., Atluri, S., and Kukreja, R. C. (2001) Mitogen-activated protein kinases mediate heat shock-induced delayed protection in mouse heart. Am. J. Physiol. Heart Circ. Physiol. 281, H523–532.
Robinson, M. J. and Cobb, M. H. (1997) Mitogen-activated protein kinase pathways. Curr. Opin. Cell Biol. 9, 180–186.
Sugden, P. H. and Bogoyevitch, M. A. (1995) Intracellular signalling through protein kinases in the heart. Cardiovasc. Res. 30, 478–492.
Marshall, C. J. (1994) MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Rev. Curr. Opin. Genet. Dev. 4, 82–89.
Minden, A., Lin, A., McMahon, M., Lange-Carter, C., Dérijard, B., Davis, R. J., et al. (1994) Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science 266, 1719–1723.
Whitmarsh, A. J., Shore, P., Sharrocks, A. D., and Davis, R. J. (1995) Integration of MAP kinase signal transduction pathways at the serum response element. Science 269, 403–407.
Lange-Carter, C. A., Pleiman, C. E., Gardner, A. M., Blumer, K. J., and Johnson, G. L. (1993) A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 260, 315–319.
Stokoe, D., Campbell, D. G., Nakielny, S., Hidaka, H., Leevers, S. J., Marshall, C., et al. (1992) MAPKAP kinase-2: A novel protein kinase activated by mitogen-activated protein kinase. EMBO J. 11, 3985–3994.
Sadoshima, J., Qiu, Z., Morgan, J. P., and Izumo, S. (1995) Angiotensin and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90 kD S6 kinase in cardiac myocytes: the critical role of Ca2+-dependent signaling. Circ. Res. 76, 1–15.
Domingos, P. P., Fonseca, P. M., Nadruz, W. Jr., and Franchini, K. G. (2002) Load-induced focal adhesion kinase activation in the myocardium: Role of stretch and contractile activity. Am. J. Physiol. 282, H556–H564.
Tahara, S., Fukuda, K., Kodama, H., Kato, T., Miyoshi, S., and Ogawa, S. (2001) Potassium channel blocker activates extracellular signal-regulated kinases through Pyk2 and epidermal growth factor receptor in rat cardiomyocytes. J. Am. Coll. Cardiol. 38, 554–563.
Ahn, N. G., Seger, R., Bratlien, R. L., Diltz, C. D., Tonks, N. K., and Krebs, E. G. (1991) Multiple components in an epidermal growth factor-stimulated protein kinase cascade. In vitro activation of a myelin basic protein/microtubule-associated protein 2 kinase. J. Biol. Chem. 266, 4220–4227.
Warne, P. H., Viciana, P. R., and Downward, J. (1993) Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364, 352–355.
Kolch, W., Heidecker, G., Kochs, G., Hummel, R., Vahidi, H., Mischak, H., et al. (1993) Protein kinase C activates Raf-1 by direct phosphorylation. Nature 364, 249–252.
Cano, E. and Mahadevan, L. C. (1995) Parallel signal processing among mammalian MAPKs. Trends Biochem. Sci. 20, 117–122.
Reszka, A. A., Seger, R., Diltz, C. D., Krebs, E. G., and Fischer, E. H. (1995) Association of mitogen-activated protein kinase with the microtubule cytoskeleton. Proc. Natl. Acad. Sci. USA 92, 8881–8885.
Erikson, R. L. (1991) Structure expression, and regulation of protein kinases involved in the phosphorylation of ribosomal protein S6. J. Biol. Chem. 266, 6007–6010.
Eldar-Finkelman, H., Seger, R., Vandenheede, J. R., and Krebs, E. G. (1995) Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J. Biol. Chem. 270, 987–990.
Frödin, M. and Gammeltoft, S. (1999) Role and regulation of 90kDa ribosomal S6 kinase (RSK) in signal transduction. Mol. Cell Endocrinol. 151, 65–77.
Lin, L. L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., and Davis, R. J. (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269–278.
Davis, R. J. (1993) The mitogen-activated protein kinase signal transduction pathway. J. Biol. Chem. 268, 14553–14556.
Lee, J. C., Laydon, J. T., McDonnell P. C., Gallagher, T. F., Kumar, S., Green, D., et al. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746.
Han, J., Lee, J. D., Bibbs, L., and Ulevitch, R. J. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–811.
Rouse, J., Cohen, P., Trigon, S., Morange, M., Alonso-Llamazares, A., Zamanillo, D., et al. (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78, 1027–1037.
Sugden, P. H. and Clerk, A. (1998) “Stress-responsive” mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardium. Circ. Res. 83, 345–352.
Zhang, S., Han, J., Sells, M. A., Chernoff, J., Knaus, U. G., Ulevitch, R. J., et al. (1995) Rho family GTP-ases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak 1. J. Biol. Chem. 270, 23934–23936.
Bagrodia, S., Derijard, B., Davis, R. J., and Cerione, R. A. (1995) Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J. Biol. Chem. 270, 27995–27998.
Fan, G., Merrit, S. E., Kortenjann, M., Shaw, P. E., and Holzman, L. B. (1996) Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38 MAPK but not ERK2. J. Biol. Chem. 271, 24788–24793.
Tibbles, L. A., Ing, Y. L., Kiefer, F., Chan, J., Iscove, N., Woodgett, J. R., et al. (1996) MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. EMBO J. 15, 7026–7035.
Freshney, N. W., Rawlinson, L., Guesdon, F., Jones, E., Cowley, S., Hsuan, J., et al. (1994) Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78, 1039–1049.
Guay, J., Lambert, H., Gingras-Breton, G., Lavoie, J. N., and Huot, J. (1997) Regulation of actin filament dynamics by p38 map kinase-mediated phosphorylation of heat shock protein 27. J. Cell Sci. 110, 357–368.
Tan, Y., Rouse, J., Zhang, A., Cariati, S., Cohen, P., and Comb, M. J. (1996) FGF and stress regulate CREB and ATF-1 via a pathway involving p38 MAP kinase and MAPKAP kinase-2. EMBO J. 15, 4629–4642.
Clerk, A., Michael, A., and Sugden, P. H. (1998) Stimulation of the p38 mitogen-activated protein kinase pathway in neonatal rat ventricular myocytes by the G protein-coupled receptor agonists, endothelin-l and phenylephrine: a role in cardiac myocyte hypertrophy? J. Cell Biol. 142, 523–535.
Raingeaud, J., Gupta, S., Rogers, J. S., Dickens, M., Han J., Ulevitch, R. J., et al. (1995) Pro-inflammatory cytokines and enviromental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. 270, 7420–7426.
Han, J., Jiang, Y., Li, Z., Kravchenko, V. V., and Ulevitch, R. J. (1997) Activation of the transcription factor MEF 2C by the MAP kinase p38 in inflammation. Nature 386, 296–299.
Pulverer, B. J., Kyriakis, J. M., Avruch, J., Nikolakaki, E., and Woodgett, J. R. (1991) Phosphorylation of c-jun mediated by MAP kinases. Nature 353, 670–674.
Derijard, B., Hibi, M., Wu, I. H., Barrett, T., Su, B., Deng, T., et al. (1994) JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76, 1025–1037.
Kyriakis, J. M., Banerjee, P., Nikolakaki, E., Dai, T., Rubie, E. A., Ahmad, M. F., et al. (1994) The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369, 156–160.
Deacon, K. and Blank, J. L. (1997) Characterization of the mitogen-activated protein kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK/p38 pathways regulated by MEK kinase 2 and 3: MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. J. Biol. Chem. 272, 14,489–14,496.
Foltz, I. N., Gerl, R.e., Wieler, J. S., Luckach, M., Salmon, R. A., and Schrader, J. W. (1998) Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (SAPK/JNK) activated by environmental stresses and physiological stimuli. J. Biol. Chem. 273, 9344–9351.
Nagao, M., Yamauchi, J., Kaziro, Y., and Itoh, H. (1998) Involvement of protein kinase C and Src family tyrosine kinase in Gαq/11–induced activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. J. Biol. Chem. 273, 22,892–22,898.
Hibi, M., Lin, A., Smeal, T., Minden, A., and Karin, M. (1993) Identification of an oncoprotein-and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7, 2135–2148.
Gupta, S., Campbell, D., Derijard, B., and Davis, R. J. (1995) Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267, 389–393.
Bogoyevitch, M. A., Ketterman, A. J., and Sugden, P. H. (1995) Cellular stresses activate c-Jun N-terminal kinases (JNKs) in ventricular myocytes cultured from neonatal rat hearts. J. Biol. Chem. 270, 29,710–29,717.
Gross, A., McDonnell, J. M., and Korsmeyer, S. J. (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911.
Lemke, L. E., Bloem, L. J., Fouts, R., Esterman, M., Sandusky, G., and Vlahos, C. J. (2001) Decreased p38 MAPK activity in end-stage failing human myocardium: p38 MAPK alpha is the predominant isoform expresed in human heart. J. Mol. Cell Cardiol. 33, 1527–1540.
Flesch, M., Margulies, K. B., Mochmann, H. C., Engel, D., Sivasubramanian, N., and Mann, D. L. (2001) Diferential regulation of mitogen-activated protein kinases in the failing human heart in response to mechanical unloading. Circulation 104, 2273–2276.
Cook, S. A., Sugden, P. H., and Clerk, A. (1999) Activation of c-Jun N-terminal kinases and p38-mitogen-activated protein kinases in human heart failure secondary to ischaemic heart disease. J. Mol. Cell Cardiol. 31, 1429–1434.
Haq S., Choukroun G., Lim H., Tymitz K. M., del Monte F., Gwathmey J., et al. (2001) Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 103, 670–677.
Takeishi, Y., Huang, Q., Abe, J., Che, W., Lee, J. D., Kawakatsu, H., et al. (2002) Activation of mitogen-activated protein kinases and p90 ribosomal S6 kinase in failing human hearts with dilated cardiomyopathy. Cardiovasc. Res. 53, 131–137.
Takeishi, Y., Huang, Q., Abe, J., Glassman, M., Che, W., Lee, J. D., et al. (2001) Src and multiple MAP kinase activation in cardiac hypertrophy and congestive heart failure under chronic pressure-overload: Comparison with acute mechanical stretch. J. Mol. Cell Cardiol. 33, 1637–1648.
Pellieux, C., Sauthier, T., Aubert, J. F., Brunner, H. R., and Pedrazzini, T. (2000) Angiotensin II-induced cardiac hypertrophy is associated with different mitogen-activated protein kinase activation in normotensive and hypertensive mice. J. Hypertens 18, 1307–1317.
Behr, T. M., Nerurkar, S. S., Nelson, A. H., Coatney, R. W., Woods, T. N., Sulpizio, A., et al. (2001) Hypertensive end-organ damage and premature mortality are p38 mitogen-activated protein kinase-dependent in a rat model of cardiac hypertrophy and dysfunction. Circulation 11, 1292–1298.
Wang, Y., Huang, S., Sah, V. P., Ross, J., Brown, J. H., Han, J., et al. (1998) Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogenactivated protein kinase family. J. Biol. Chem. 273, 2161–2168.
Liao, P., Georgakopoulos, D., Kovacs, A., Zheng, M., Lerner, D., Pu, H., et al. (2001) The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc. Natl. Acad. Sci. USA 9, 12,283–12,288.
Wang, Y., Su, B., Sah, V. P., Brown, J. H., Han, J., and Chien, K. R. (1998) Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. J. Biol. Chem. 273, 5423–5426.
Finn, S. G., Dickens, M., and Fuller, S. J. (2001) c-Jun N-terminal kinase/interacting protein 1 inhibits gene expression in response to hypertrophic agonists in neonatal rat ventricular myocytes. Biochem. J. 358, 489–495.
Choukroun, G., Hajjar, R., Kyriakis, J. M., Bonventre, J. V., Rosenzweig, A., and Force, T. (1998) Role of the stress-activated protein kinases in endothelin-induced cardiomyocyte hypertrophy. J. Clin. Invest. 102, 1311–1320.
Yue, T. L., Gu, J. L., Wang, C., Reith, A. D., Lee, J. C., Mirabile, R. C., et al. (2000) Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. J. Biol. Chem. 275, 37,895–37,901.
Bueno, O. F., De Windt, L. J., Tymitz, K. M., Witt, S. A., Kimball, T. R., Klevitsky, R., et al. (2000) The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. EMBO J. 19, 6341–6350.
Glennon, P. E., Kaddoura, S., Sale, E. M., Sale, G. J., Fuller, S. J., and Sugden, P. H. (1996) Depletion of mitogen-activated protein kinase using an antisense oligodeoxynucleotide approach downregulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. Circ. Res. 78, 954–961.
Kang Y. J., Zhou Z. X., Wang G. W., Buridi A., and Klein J. B. (2000) Suppression by metallothionein of doxorubicin-induced cardiomyocyte apoptosis through inhibition of p38 mitogen-activated protein kinases. J. Biol. Chem. 275, 1390–1398.
Schneider, S. Chen W, Hou J, Steenbergen C, and Murphy E. (2001) Inhibition of p38 MAPK alpha/beta reduces ischemic injury and does not block protective effects of preconditioning. Am. J. Physiol. Heart Circ. Physiol. 280, H499–508.
Ma, XL., Kumar, S., Gao, F., Louden, C. S., Lopez, B. L., Christopher, T. A., et al. (1999) Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation 99, 1685–1691.
Gysembergh, A., Simkhovich, B. Z., Kloner, R. A., and Przyklenk, K. (2001) p38 MAPK activity is not increased early during sustained coronary artery occlusion in preconditioned versus control rabbit heart. J. Mol. Cell Cardiol. 33, 681–690.
Marais, E., Genade, S., Huisamen, B., Strijdom, J. G., Moolman, J. A., and Lochner, A. (2001) Activation of p38 MAPK induced by a multi-cycle ischaemic preconditioning protocol is associated with attenuated p38 MAPK activity during sustained ischaemia and reperfusion. J. Mol. Cell Cardiol. 33, 769–778.
Barancik, M., Htun, P., Strohm, C., Kilian, S., and Schaper, W. (2000) Inhibition of the cardiac p38-MAPK pathway by SB203580 delays ischemic cell death. J. Cardiovasc. Pharmacol. 35, 474–483.
Cain, B. S., Meldrum, D. R., Meng, X., Dinarello, C. A., Shames, B. D., Banerjee, A., et al. (1999) p38 MAPK inhibition decreases TNF-alpha production and enhances postischemic human myocardial function. J. Surg. Res. 83, 7–12.
Fijen, J. W., Zijlstra, J. G., De Boer, P., Spanjersberg, R., Cohen Tervaert, J. W., Van Der Werf, T. S., et al. (2001) Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin. Exp. Immunol. 124, 16–20.
Yamazaki, T., Tobe, K., Hoh, E., Maemura, K., Kaida, T., Komuro, I., et al. (1993) Mechanical loading activates mitogen-activated protein kinase and S6 peptide kinase in cultured rat cardiac myocytes. J. Biol. Chem. 268, 12,069–12,076.
Kudoh, S., Komuro, I., Hiroi, Y., Zou, Y., Harada, K., Sugaya, T., et al. (1998) Mechanical stretch induces hypertrophic responses in cardiac myocytes of angiotensin II type 1a receptor knockout mice. J. Biol. Chem. 273, 24,037–24,043.
Hayashida, W., Kihara, Y., Yasaka, A., Inagaki, K., Iwanaga, Y., and Sasayama, S. (2001) Stage-specific differential activation of mitogen-activated protein kinases in hypertrophied and failing rat hearts. J. Mol. Cell Cardiol. 33, 733–744.
Lazou, A., Sugden, P. H., and Clerk, A. (1998) Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart. Biochem. J. 332, 459–465.
Ng, D. C., Long, C. S., and Bogoyevitch, M. A. (2001) A role for the extracellular signal-regulated kinase and p38 mitogen-activated protein kinases in interleukin-1 beta-stimulated delayed signal tranducer and activator of transcription 3 activation, atrial natriuretic factor expression, and cardiac myocyte morphology. J. Biol. Chem. 276, 29,490–29,498.
Clerk, A., Bogoyevitch, M. A., Anderson, M. B., and Sugden, P. H. (1994) Differential activation of protein kinase C isoforms by endothelin-1 and phenylephrine, and subsequent stimulation of p42 and p44 mitogen-activated protein kinases in ventricular myocytes cultured from neonatal rat hearts. J. Biol. Chem. 269, 32,848–32,857.
Xiao, L., Pimental, D. R., Amin, J. K., Singh, K., Sawyer, D. B., and Colucci, W. S. (2001) MEK1/2-ERK1/2 mediates alpha1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J. Mol. Cell Cardiol. 33, 779–787.
Bueno, O. F., De Windt, L. J., Lim, H. W., Tymitz, K. M., Witt, S. A., Kimball, T. R., et al. (2001) The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo. Circ. Res. 88, 88–96.
Barancik, M., Htun, P., Maeno, Y., Zimmermann, R., and Shaper, W. (1997) Differential regulation of distinct protein kinase cascades by ischemia and ischemia/reperfusion in porcine myocardium (asbtr.). Circulation 96, I–252.
Behrends, M., Schulz, R., Post, H., Alexandrov, A., Belosjorow, S., Michel, M. C., et al. (2000) Inconsistent relation of MAPK activation to infarct size reduction by ischemic preconditioning in pigs. Am. J. Physiol. Heart Circ. Physiol. 279, H1111–1119.
Araujo, E. G., Bianchi, C., Faro, R., and Sellke, F. W. (2001) Oscilation in the activities of MEK/ERK1/2 during cardiopulmonary bypass in pigs. Surgery 130, 182–191.
Yoshida, K., Yoshiyama, M., Omura, T., Nakamura, Y., Kim, S., Takeuchi, K., et al. (2001) Activation of mitogen-activated protein kinases in the non-ischemic myocardium of an acute myocardial infarction in rats. Jpn. Circ. J. 65, 808–814.
Knight, R. J. and Buxton, D. B. (1996) Stimulation of c-Jun kinase and mitogen-activated protein kinase by ischemia and reperfusion in the perfused rat hearts. Biochem. Biophys. Res. Commun. 218, 83–88.
Takeishi, Y., Huang, Q., Wang, T., Glassman, M., Yoshizumi, M., Baines, C. P., et al. (2001) Src family kinase and adenosine differentially regulate multiple MAP kinases in ischemic myocardium: Modulation of MAP kinases activation by ischemic preconditioning. J. Mol. Cell Cardiol. 33, 1989–2005.
Bogoyevitch, M. A., Gillespie-Brown, J., Ketterman, A. J., Fuller, S. J., Ben-Levy, R., Ashworth, A., et al. (1996) Stimulation of the stress-activated mitogen-activated protein kinases subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-jun N-terminal kinases are activated by ischemia/reperfusion. Circ. Res. 79, 162–173.
Ping, P., Zhang, J., Cao, X., Kong, D., Tang, X. L., Qiu, Y., et al. (1999) PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am. J. Physiol. Heart Circ. Physiol. 276, H1468–1481.
Fryer, R. M., Hsu, A. K., and Gross, G. J. (2001) ERK and p38 MAP kinase activation are components of opioid-induced delayed cardioprotection. Basic Res. Cardiol. 96, 136–142.
Buerke, M., Murohara, T., Skurk, C., Nuss, C., Tomaselli, K., and Lefer, A. (1995) Cardioprotective effect of insulin-like growth factor I in myocardial ischemia followed by reperfusion. Proc. Natl. Acad. Sci. USA 92, 8031–8035.
Parrizas, M., Saltiel, A. R., and LeRoith, D. (1997) Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3′-kinase and mitogen-activated protein kinase pathways. J. Biol. Chem. 272, 154–161.
Vogt, A., Htun, P., Kluge, A., Zimmermann, R., and Schaper, W. (1997) Insulin like growth factor II delays myocardial infarction in experimental coronary artery occlusion. Cardiovasc. Res. 33, 469–477.
Htun, P., Ito, W. D., Hoefer, I. E., Schaper, J., and Schaper, W. (1998) Intramyocardial infusion of FGF-1 mimics ischemic preconditioning in pig myocardium. J. Mol. Cell Cardiol. 30, 867–877.
Padua, R. R., Sethi, R., Dhalla, N. S., and Kardami, E. (1995) Basic fibroblast growth factor is cardioprotective in ischemia-reperfusion injury. Mol. Cell. Biochem. 143, 129–135.
Ghosh, S., Ng, L. L., Talwar, S., Squire, I. B., and Galinanes, M. (2000) Cardiotrophin-1 protects the human myocardium from ischemic injury: Comparison with the first and second window of protection by ischemic preconditioning. Cardiovasc. Res. 48, 440–447.
Kuwahara, K., Saito, Y., Kishimoto, I., Miyamoto, Y., Harada, M., Ogawa, E., et al. (2000) Cardiotrophin-1 phosphorylates Akt and BAD, and prolongs cell survival via a PI3K-dependent pathway in cardiac myocytes. J. Mol. Cell Cardiol. 32, 1385–1394.
Bogoyevitch, M. A., Glennon, P. E., Andersson, M. B., Clerk, A., Lazou, A., Marshall, C. J., et al. (1994) Endothelin-1 and fibroblast growth factors stimulate the mitogen-activated protein kinase signaling cascade in cardiac myocytes. The potential role of the cascade in the integration of two signaling pathways leading to myocyte hypertrophy. J. Biol. Chem. 269, 1110–1119.
Stephanou, A., Brar, B., Heads, R., Knight, R. D., Marber, M. S., Pennica, D., et al. (1998) Cardiotrophin-1 induces heat shock protein accumulation in cultured cardiac cells and protects them from stressful stimuli. J. Mol. Cardiol. 30, 849–855.
Sheng, Z., Knowlton, K., Chen, J., Hoshijima, M., Brown, J. H., and Chien, K. R. (1997) Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J. Biol. Chem. 272, 5783–5791.
Weinbrenner, C., Liu, G. S., Cohen, M. V., and Downey, J. M. (1997) Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in rabbit heart. J. Mol. Cell Cardiol. 29, 2383–2391.
Nakano, A., Baines, C. P., Kim, C. O., Pelech, S. L., Downey, J. M., Cohen, M. V., et al. (2000) Ischemic preconditioning activates MAPKAPK2 in isolated rabbit heart. Evidence for involvement of p38 MAPK. Circ. Res. 86, 144–151.
Armstrong, S. C., Delacey, M., and Ganote, C. E. (1999) Phosphorylation state of hsp27 and p38 MAPK during preconditioning and protein phosphatase inhibitor protection of rabbit cardiomyocytes. J. Mol. Cell Cardiol. 31, 555–567.
Sato, M., Cordis, G. A., Maulik, N., and Das, D. K. (2000) SAPKs regulation of ischemic preconditioning. Am. J. Physiol. Heart Circ. Physiol. 279, H901–907.
Yue, T. L., Wang, C., Gu, J. L., Ma, X. L., Kumar, S., Lee, J. C., et al. (2000) Inhibition of extracellular signal-regulated kinase enhances ischemia/reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ. Res. 86, 692–699.
Nakano, A., Cohen, M. V., Critz, S., and Downey, J. M. (2000) SB 203580, an inhibitor of p38 MAPK, abolishes infarct-limiting effect of ischemic preconditioning in isolated rabbit hearts. Basic Res. Cardiol. 95, 466–471.
Mocanu, M. M., Baxter, G. F., Yue, Y., Critz, S. D., and Yellon, D. M. (2000) The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical. Basic Res. Cardiol. 95, 472–478.
Murry, C. E., Jennings, R. B., and Reimer, K. A. (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74, 1124–1136.
Cohen, M. V., Baines, Ch. P., and Downey, J. M. (2000) Ischemic Preconditioning: From adenosine receptor to KATP Channel. Annu. Rev. Physiol. 62, 79–109.
Fryer, R. M., Pratt, P. F., Hsu, A. K., and Gross, G. J. (2001) Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection. J. Pharmacol. Exp. Ther. 296, 642–649.
Maulik, N., Watanabe, M., Zu, Y. L., Huang, C. K., Cordis, G. A., Schley, J. A., et al. (1996) Ischemic preconditioning triggers the activation of MAP kinases and MAPKAP kinase 2 in rat heart. FEBS Lett. 396, 233–237.
Martin, J. L., Avkiran, M., Quinlan, R. A., Cohen, P., and Marber, M. S. (2001) Antiischemic effects of SB203580 are mediated through the inhibition of p38alpha mitogen-activated protein kinase: evidence from ectopic expression of an inhibition-resistant kinase. Circ. Res. 89, 750–752.
Saurin, A. T., Martin, J. L., Heads, R. J., Foley, C., Mockridge, J. W., Wright, M. J., et al. (2000) The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB J. 14, 2237–2246.
Fryer, R. M., Patel, H. H., Hsu, A. K., and Gross, G. J. (2001) Stress-activated protein kinase phosphorylation during cardioprotection in the ischemic myocardium. Am. J. Physiol. Heart Circ. Physiol. 281, H1184–1192.
Barancik, M., Htun, P., and Schaper, W. (1999) Okadaic acid and anisomycin are protective and stimulate the SAPK/JNK pathway. J. Cardiovasc. Pharmacol. 34, 182–190.
Mackay, K. and Mochly-Rosen, D. (1999) An inhibitor of p38 mitogen-activated protein kinase protects neonatal rat cardiac myocytes from ischemia. J. Biol. Chem. 274, 6272–6279.
Yellon, D. M. and Baxter, G. F. (1995) “A second window of protection” or delayed preconditioning phenomenon: Future horizons for myocardial protection. J. Mol. Cell Cardiol. 27, 1023–1034.
Zhao, T. C., Taher, M. M., Valerie, K. C., and Kukreja, R. C. (2001) p38 triggers late preconditioning elicited by anisomycin in heart: Involvement of NF-kappaB and iNOS. Circ. Res. 89, 915–922.
Wilson, S., Wu, S., Kaszala, K., Ravingerova, T., Vegh, A., Papp, J., et al. (1996) Delayed cardioprotection is associated with the subcellular relocalisation of ventricular protein kinase Cε, but not p42/44MAPK. Mol. Cell Biochem. 161, 225–230.
Alessi, D. R., Cuenda, A., Cohen, P., Dudley, D. T., and Saltiel, A. R. (1995) PD 098059 is a specific inhibitor of activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270, 27,489–27,494.
Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., et al. (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632.
Kamakura, S., Moriguchi, T., and Nishida, E. (1999) Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. J. Biol. Chem. 274, 26,563–26,571.
Tong, L., Pav, S., White, D., Rogers, S., Crane, K. M., Cywin, C. L., et al. (1997) A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nat. Struct. Biol. 4, 311–316.
Kumar, S., Jiang, M. S., Adams, J. L., and Lee, J. C. (1999) Pyridinylimidazole compound SB 203580 inhibits the activity but not the activation of p38 mitogen-activated protein kinase. Biochem. Biophys. Res. Commun. 263, 825–831.
Sakamoto, K., Urushidani, T., and Nagao, T. (2000) Translocation of HSP27 to sarcomere induced by ischemic preconditioning in isolated rat hearts. Biochem. Biophys. Res. Commun. 269, 137–142.
Ballard-Croft, C., White, D. J., Maass, D. L., Hybki, D. P., and Horton, J. W. (2001) Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-alpha. Am. J. Physiol. Heart Circ. Physiol. 280, H1970–1981.
Brar, B. K., Jonassen, A. K., Stephanou, A., Santilli, G., Railson, J., Knight, R. A., et al. (2000) Urocortin protects against ischemia and reperfusion injury via a MAPK-dependent pathway. J. Biol. Chem. 275, 8508–8514.
Xie, Z., Pimental, D. R., Lohan, S., Vasertriger, A., Pligavko, C., Colucci, W. S., et al. (2001) Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: Role of p42/44 mitogen-activated protein kinase and reactive oxygen species. J. Cell Physiol. 188, 132–138.
van Eickels, M., Grohe, C., Lobbert, K., Stimpel, M., and Vetter, H. (1999) Angiotensin converting enzyme inhibitors block mitogenic signalling pathways in rat cardiac fibro-blasts. Naunyn Schmiedebergs Arch. Pharmacol. 359, 394–399.
Kim, S., Izumi, Y., Yano, M., Hamaguchi, A., Miura, K., Yamanaka, S., et al. (1998) Angiotensin blockade inhibits activation of mitogen-activated protein kinases in rat balloon-injured artery. Circulation 97, 1731–1737.
Yue, T. L., Ma, X. L., Wang, X., Romanic, A. M., Liu, G. L., Louden, C., et al. (1998) Possible involvement of stress-activated protein kinase signaling pathway and Fas receptor expression in prevention of ischemia/reperfusion-induced cardiomyocyte apoptosis by carvedilol. Circ. Res. 82, 166–174.
Chesley, A., Lundberg, M. S., Asai, T., Xiao, R. P., Ohtani, S., Lakatta, E. G., et al. (2000) The beta(2)-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through G(i)-dependent coupling to phosphatidylinositol 3′-kinase. Circ. Res. 87, 1172–1179.
Hanford, D. S. and Glembotski, C. C. (1996) Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: Potential roles for protein kinase C and mitogen-activated protein kinase. Mol. Endocrinol. 10, 1719–1727.
Cano, E., Doza, Y. N., Ben-Levy, R., Cohen, P., and Mahadevan, L. C. (1996) Identification of anisomycin-activated kinases p45 and p55 in murine cells as MAPKAP kinase-2. Oncogene 12, 805–812.
Baines, C. P., Wang, L., Cohen, M. V., and Downey, J. M. (1998) Protein tyrosine kinase is downstream of protein kinase C for ischemic preconditioning’s anti-infarct effect in the rabbit heart. J. Mol. Cell Cardiol. 30, 383–392.
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Ravingerova, T., Barancik, M., Strniskova, M. (2003). Mitogen-Activated Protein Kinases-Mediated Signaling in Cardiac Pathology. In: Pugsley, M.K. (eds) Cardiac Drug Development Guide. Methods in Pharmacology and Toxicology. Humana Press. https://doi.org/10.1385/1-59259-404-2:67
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