Abstract
The signal transduction pathways triggering apoptotic mechanisms after ischemia/reperfusion may involve TNF-α secretion, ceramide generation, and initiation of lipid peroxidation. In the present study involvement of the TNF-α, sphingomyelin cycle, and lipid peroxidation in the initiation of apoptosis induced in liver cells by ischemia and reperfusion was investigated. Wistar rats were subjected to total liver ischemia (for 15, 30 min, and 1 h) followed by subsequent reperfusion. Ischemia caused sharp decrease of neutral sphingomyelinase activity. Activity of acidic sphingomyelinase initially decreased (during 15-30 min ischemia) but then increased (after 1 h of ischemic injury). Reperfusion of the ischemic lobe of the liver caused increase in neutral sphingomyelinase activity and decrease in acidic sphingomyelinase activity. A small amount of TNF-α detected by immunoblotting analysis was accumulated in the ischemic area of liver rapidly and the content of this cytokine dramatically increased after the reperfusion. TNF-α is known to induce free radical production. We found that the accumulation of TNF and increase of sphingomyelinase activity during the development of ischemic/reperfusion injury coincided with increase in content of lipid peroxidation products (conjugated dienes) and DNA degradation detected by gel electrophoresis. Recently it was shown that superoxide radicals are used as signaling molecules within the sphingomyelin pathway. This suggests the existence of cross-talk between the oxidation system and the sphingomyelin cycle in cells, which may have important implications for the initial phase and subsequent development of post-ischemic injury.
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REFERENCES
Bilzer, M., and Gerbes, A. J. (2000) Hepatology, 32, 508-515.
Kaplowitz, N. J. (2000) Hepatology, 32, Suppl. 1, 39-47.
Zager, R. A., Iwata, M., Conrad, D. S., Burhart, K. M., and Igarashi, Y. (1997) Kidney Int. 52, 60-70.
Bielawska, A. E., Shapiro, J. P., Jiang, L., Melkonyan, H. S., Piot, C., Wolfe, C. L., Tomei, L. D., Hannun, Y. A., and Umansky, S. R. (1997) Am. J. Pathol., 151, 1257-1263.
Yu. Z. F., Nikolova-Karakashian, M., Zhou, D., Cheng, G., Schuchman, E. H., and Mattson, M. P. (2000) J. Mol. Neurosci., 15, 85-97.
Leist, M., Gantner, F., Bohlinger, I., Germann, P. G., Tiegs, G., and Wendel, A. (1994) J. Immunol., 153, 1778-1788.
Andus, T., and Holstege, A. (1994) Acta Gastroenterol. Belg., 57, 236-244.
Alessenko, A. V., Platonova, L. V., Sekevarashvili, G. R., Khrenov, A. V., Shingarova, L. N., Shono, N. I., and Galperin, E. I. (1999) Biochemistry (Moscow), 64, 890-895.
Alessenko, A. V., Khrenov, A. V., Soloviev, A. S., and Terentiev, A. A. (1998) Izv. Akad. Nauk, Biol. Ser., No. 2, 157-166.
Alessenko, A. V., and Khrenov, A. V. (1999) Lipids, 34, 75-76.
Alessenko, A. V. (1999) Biol. Membr. (Moscow), 16, 242-255.
Schutze, S., Potthoff, K., Machleidt, T., Dorge, J., Berkovic, D., Wiegmann, K., and Kronke, M. (1992) Cell, 71, 765-776.
Sosnowski, J., Stetter-Neel, C., Cole, D., Durham, J. P., and Mawhinney, M. G. (1997) J. Urol., 158, 269-274.
Swartz, G. K. (1995) J. Natl. Cancer Inst., 87, 1394-1399.
Spence, M. W. (1993) Adv. Lipid Res., 26, 3-23.
Levade, T., and Jaffrezou, J.-P. (1999) Biochim. Biophys. Acta, 1438, 1-17.
Takeda, Y., Tashima, M., Takahashi, A., Uchiyama, T., and Okazaki, T. (1999) J. Biol. Chem., 274, 10654-10660.
Aggarwal, B., and Natarajan, K. (1996) Eur. Cytokine Netw., 7, 93-124.
Garcia-Ruiz, C., Mari, M., Morales, A., Colell, A., Ardite, E., and Fernandez-Checa, J. C. (2000) Hepatology, 32, 56-65.
Liu, B., Hassler, D. F., Smith, G. K., Weaver, K., and Hannun, Y. A. (1998) J. Biol. Chem., 273, 34472-34479.
Zyupko, A. N., Dudnik, L. B., Evstigneeva, R. P., and Alessenko, A. V. (2001) Biochemistry (Moscow), 66, 1028-1034.
Dudnik, L. B., Zyupko, A. N., Shupik, M. A., and Alessenko, A. V. (2001) Chemistry and Physics of Lipids, 110, 123-124.
Laemmli, U. K. (1979) Nature, 227, 680-685.
Hostetler, K., and Yasaki, P. (1979) J. Lipid Res., 20, 456-463.
Bligh, T. G., and Dyer, W. J. (1959) Canad. J. Biochem. Physiol., 37, 911-917.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951) J. Biol. Chem., 193, 265-275.
Stalnaya, I. D., and Garishvili, T. G. (1977) in Modern Methods in Biochemistry (Orekhovich, V. N., ed.) [in Russian], Nauka, Moscow, pp. 63-64.
Herrmann, M., Lorenz, H. M., Voll, R., Woith, W., Grunke, M., and Kalden, J. R. (1994) Nucleic Acids Res., 22, 5506-5507.
Cummings, B. S., McHowat, J., and Schnellmann, R. G. (2000) J. Pharmacol. Exp. Ther., 294, 793-799.
Nishiyama, R., Nakamura, S., Suzuki, S., and Baba, S. (1993) Transplantation, 55, 1261-1265.
Obeid, L. M., Linardic, C. M., Koralak, L. A., and Hannun, Y. A. (1993) Science, 259, 1769-1771.
Ohta, H., Yatomi, Y., Sweeney, E. A., Hakomori, S., and Igarashi, Y. A. (1994) FEBS Lett., 355, 267-270.
Krown, K. A., Page, M. T., Nguyen, C., Zechner, D., Gutierrez, V., Comstock, K. L., Glembotski, C. C., Quintana, P. J., and Sabbadini, R. A. (1996) J. Clin. Invest., 98, 2854-2865.
Zager, R. A., Conrad, S., Lochhead, K., Sweeney, E. A., Igarashi, Y., and Burkhart, K. M. (1998) Kidney Int., 53, 573-582.
Cordis, G. A., Yoshida, T., and Das, D. K. (1998) J. Pharm. Biomed. Anal., 16, 1189-1193.
Meldrum, D. R. (1998) Am. J. Physiol., 274 (3Pt. 2), R577-595.
Chandrasekar, B., Colston, J. T., and Freeman, G. L. (1997) Clin. Exp. Immunol., 108, 346-351.
Nossuli, T. O., Lakshminarayanan, V., Baumgarten, G., Taffet, G. E., Ballantyne, C. M., Michael, L. H., and Entman, M. L. (2000) Am. J. Physiol. Heart. Circ. Physiol., 278, H1017-1018.
Dinarello, C. A., and Pomerantz, B. J. (2001) Blood Purif., 19, 314-321.
Heba, G., Krzeminski, T., Pore, M., Grzyb, J., and Dembinska-Kiee, A. (2001) J. Physiol. Pharmacol., 52, 39-52.
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Alessenko, A.V., Galperin, E.I., Dudnik, L.B. et al. Role of Tumor Necrosis Factor Alpha and Sphingomyelin Cycle Activation in the Induction of Apoptosis by Ischemia/Reperfusion of the Liver. Biochemistry (Moscow) 67, 1347–1355 (2002). https://doi.org/10.1023/A:1021853825244
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DOI: https://doi.org/10.1023/A:1021853825244