Background. Global myocardial ischemia reperfusion injury after heart transplantation is believed to impair graft function and aggravate both acute and chronic rejection episodes. Objectives. To assess the possible protective potential of MK-886 and 3,5-diiodothyropropionic acid DITPA against global myocardial ischemia reperfusion injury after heart transplantation. Materials and Methods. Adult albino rats were randomized into 6 groups as follows: group I sham group; group II, control group; groups III and IV, control vehicles (1,2); group V, MK-886 treated group. Donor rats received MK-886 30?min before transplantation, and the same dose was repeated for recipients upon reperfusion; in group VI, DITPA treated group, donors and recipients rats were pretreated with DITPA for 7 days before transplantation. Results. Both MK-886 and DITPA significantly counteract the increase in the levels of cardiac TNF-α, IL-1β, and ICAM-1 and plasma level of cTnI ( ). Morphologic analysis showed that both MK-886 and DITPA markedly improved ( ) the severity of cardiac injury in the heterotopically transplanted rats. Conclusions. The results of our study reveal that both MK-886 and DITPA may ameliorate global myocardial ischemia reperfusion injury after heart transplantation via interfering with inflammatory pathway. 1. Introduction Organ transplantation is a unique situation where grafts are successively subjected to global cold ischemia, warm ischemia, and blood reperfusion. These events are believed to impair graft function and aggravate both acute and chronic rejection episodes [1, 2]. The pathophysiology of ischemia/reperfusion (I/R) injury shows several characteristics of inflammatory responses including activation of complement, platelets, and endothelial cells, infiltration of monocytes and neutrophils, and the release of oxygen-derived-free radicals, chemokines, and cytokines [3]. MK-886 is a highly potent inhibitor of leukotriene formation in vivo and in vitro [4]. This compound inhibits leukotriene biosynthesis indirectly by a mechanism through the binding of a membrane-bound 5-lipoxygenase-activating protein (FLAP), thereby inhibiting the translocation and activation of 5-lipoxygenase [5, 6]. MK-886 was found to prevent both post ischemic leukotriene accumulation and the microcirculatory changes after ischemia-reperfusion [7]. MK-886 was also found to be effective in prevention of liver and intestine injury by reducing apoptosis and oxidative stress in a hepatic I/R model. Anti-inflammatory properties and inhibition of lipid peroxidation by MK-886 could be
References
[1]
W. Land and K. Messmer, “The impact of ischemia/reperfusion injury on specific and non-specific, early and late chronic events after organ transplantation,” Transplantation Reviews, vol. 10, no. 2, pp. 108–127, 1996.
[2]
W. Land, H. Schneeberger, S. Schleibner et al., “The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants,” Transplantation, vol. 57, no. 2, pp. 211–217, 1994.
[3]
H. S. Sharma and D. K. Das, “Role of cytokines in myocardial ischemia and reperfusion,” Mediators of Inflammation, vol. 6, no. 3, pp. 175–183, 1997.
[4]
J. Gillard, A. W. Ford-Hutchinson, C. Chan et al., “L-663,536 (MK-886) (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid), a novel, orally active leukotriene biosynthesis inhibitor,” Canadian Journal of Physiology and Pharmacology, vol. 67, no. 5, pp. 456–464, 1989.
[5]
P. J. Vickers, “5-Lipoxygenase-activating protein (FLAP),” Journal of Lipid Mediators and Cell Signalling, vol. 12, no. 2-3, pp. 185–194, 1995.
[6]
C. A. Rouzer, A. W. Ford-Hutchinson, H. E. Morton, and J. W. Gillard, “MK886, a potent and specific leukotriene biosynthesis inhibitor blocks and reverses the membrane association of 5-lipoxygenase in ionophore-challenged leukocytes,” The Journal of Biological Chemistry, vol. 265, no. 3, pp. 1436–1442, 1990.
[7]
H. A. Lehr, A. Guhlmann, D. Nolte, D. Keppler, and K. Messmer, “Leukotrienes as mediators in ischemia-reperfusion injury in a microcirculation model in the hamster,” Journal of Clinical Investigation, vol. 87, no. 6, pp. 2036–2041, 1991.
[8]
G. Daglar, T. Karaca, Y. N. Yuksek et al., “Effect of montelukast and MK-886 on hepatic ischemia-reperfusion injury in rats,” Journal of Surgical Research, vol. 153, no. 1, pp. 31–38, 2009.
[9]
M. J. Eppihimer, J. Russell, D. C. Anderson, C. J. Epstein, S. Laroux, and D. N. Granger, “Modulation of P-selectin expression in the postischemic intestinal microvasculature,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 273, no. 6, pp. G1326–G1332, 1997.
[10]
G. D. Pennock, T. E. Raya, J. J. Bahl, S. Goldman, and E. Morkin, “Cardiac effects of 3,5-diiodothyropropionic acid, a thyroid hormone analog with inotropic selectivity,” Journal of Pharmacology and Experimental Therapeutics, vol. 263, no. 1, pp. 163–169, 1992.
[11]
E. Morkin, G. D. Pennock, P. H. Spooner, J. J. Bahl, and S. Goldman, “Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure,” Thyroid, vol. 12, no. 6, pp. 527–533, 2002.
[12]
S. A. Mousa, L. O'Connor, F. B. Davis, and P. J. Davis, “Proangiogenesis action of the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) is initiated at the cell surface and is integrin mediated,” Endocrinology, vol. 147, no. 4, pp. 1602–1607, 2006.
[13]
A. A. Abohashem-Aly, X. Meng, J. Li et al., “DITPA, a thyroid hormone analog, reduces infarct size and attenuates the inflammatory response following myocardial ischemia,” Journal of Surgical Research, vol. 171, no. 2, pp. 379–385, 2011.
[14]
N. Maitra, C. Adamson, K. Greer et al., “Regulation of gene expression in rats with heart failure treated with the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) and the combination of DITPA and captopril,” Journal of Cardiovascular Pharmacology, vol. 50, no. 5, pp. 526–534, 2007.
[15]
D. Wiedemann, S. Schneeberger, P. Friedl et al., “The fibrin-derived peptide Bβ15–42 significantly attenuates ischemia-reperfusion injury in a cardiac transplant model,” Transplantation, vol. 89, no. 7, pp. 824–829, 2010.
[16]
D. Xiu, H. Uchida, H. To et al., “Simplified method of heterotopic rat heart transplantation using the cuff technique: application to sublethal dose protocol of methotrexate on allograft survival,” Microsurgery, vol. 21, no. 1, pp. 16–21, 2001.
[17]
M. Zhang, Y. Xu, H. K. Saini, B. Turan, P. P. Liu, and N. S. Dhalla, “Pentoxifylline attenuates cardiac dysfunction and reduces TNF-α level in ischemic-reperfused heart,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 289, no. 2, pp. H832–H839, 2005.
[18]
B. Zingarelli, A. L. Salzman, and C. Szabó, “Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury,” Circulation Research, vol. 83, no. 1, pp. 85–94, 1998.
[19]
D. R. Meldrum, “Tumor necrosis factor in the heart,” The American Journal of Physiology, vol. 274, no. 3, pp. R577–R595, 1998.
[20]
J. Gurevitch, I. Frolkis, Y. Yuhas et al., “Tumor necrosis factor-alpha is released from the isolated heart undergoing ischemia and reperfusion,” Journal of the American College of Cardiology, vol. 28, no. 1, pp. 247–252, 1996.
[21]
D. R. Meldrum, J. C. Cleveland Jr., B. S. Cain, X. Meng, and A. H. Harken, “Increased myocardial tumor necrosis factor-α in a crystalloid-perfused model of cardiac ischemia-reperfusion injury,” Annals of Thoracic Surgery, vol. 65, no. 2, pp. 439–443, 1998.
[22]
N. G. Frangogiannis, M. L. Lindsey, L. H. Michael et al., “Resident cardiac mast cells degranulate and release preformed TNF-α, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion,” Circulation, vol. 98, no. 7, pp. 699–710, 1998.
[23]
C. Kupatt, H. Habazettl, A. Goedecke et al., “Tumor necrosis factor-α contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts,” Circulation Research, vol. 84, no. 4, pp. 392–400, 1999.
[24]
M. W. Irwin, S. Mak, D. L. Mann et al., “Tissue expression and immunolocalization of tumor necrosis factor-α in postinfarction dysfunctional myocardium,” Circulation, vol. 99, no. 11, pp. 1492–1498, 1999.
[25]
J. M. Brown, L. S. Terada, M. A. Grosso et al., “Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts,” Journal of Clinical Investigation, vol. 81, no. 4, pp. 1297–1301, 1988.
[26]
K. Z. Guyton, Y. Liu, M. Gorospe, Q. Xu, and N. J. Holbrook, “Activation of mitogen-activated protein kinase by H2O2: role in cell survival following oxidant injury,” The Journal of Biological Chemistry, vol. 271, no. 8, pp. 4138–4142, 1996.
[27]
A. Herskowitz, S. Choi, A. A. Ansari, and S. Wesselingh, “Cytokine mRNA expression in postischemic/reperfused myocardium,” The American Journal of Pathology, vol. 146, no. 2, pp. 419–428, 1995.
[28]
J. Lutz, K. Thürmel, and U. Heemann, “Anti-inflammatory treatment strategies for ischemia/reperfusion injury in transplantation,” Journal of Inflammation, vol. 7, article 27, 2010.
[29]
G. L. Kukielka, H. K. Hawkins, L. Michael et al., “Regulation of intercellular adhesion molecule-1 (ICAM-1) in ischemic and reperfused canine myocardium,” Journal of Clinical Investigation, vol. 92, no. 3, pp. 1504–1516, 1993.
[30]
N. G. Frangogiannis, C. W. Smith, and M. L. Entman, “The inflammatory response in myocardial infarction,” Cardiovascular Research, vol. 53, no. 1, pp. 31–47, 2002.
[31]
J. Bertinchant, A. Polge, E. Robert et al., “Time-course of cardiac troponin I release from isolated perfused rat hearts during hypoxia/reoxygenation and ischemia/reperfusion,” Clinica Chimica Acta, vol. 283, no. 1-2, pp. 43–56, 1999.
[32]
P. O. Collinson, F. G. Boa, and D. C. Gaze, “Measurement of cardiac troponins,” Annals of Clinical Biochemistry, vol. 38, no. 5, pp. 423–449, 2001.
[33]
R. Bolli and E. Marbán, “Molecular and cellular mechanisms of myocardial stunning,” Physiological Reviews, vol. 79, no. 2, pp. 609–634, 1999.
[34]
B. Zingarelli, P. W. Hake, A. Denenberg, and H. R. Wong, “Sesquiterpene lactone parthenolide, an inhibitor of IκB kinase complex and nuclear factor-κB, exerts beneficial effects in myocardial reperfusion injury,” Shock, vol. 17, no. 2, pp. 127–134, 2002.
[35]
C. Duilio, G. Ambrosio, P. Kuppusamy, A. Dipaula, L. C. Becker, and J. L. Zweier, “Neutrophils are primary source of O2 radicals during reperfusion after prolonged myocardial ischemia,” The American Journal of Physiology—Heart and Circulatory Physiology, vol. 280, no. 6, pp. H2649–H2657, 2001.
[36]
G. Ambrosio and I. Tritto, “Reperfusion injury: experimental evidence and clinical implications,” The American Heart Journal, vol. 138, no. 2, part 2, pp. S69–S75, 1999.
[37]
F. G. Al-Amran, N. R. Hadi, and A. M. Hashim, “Leukotriene biosynthesis inhibition ameliorates acute lung injury following hemorrhagic shock in rats,” Journal of Cardiothoracic Surgery, vol. 6, no. 1, article 81, 2011.
[38]
Y. Wang, B. Zhou, J. Li et al., “Inhibitors of 5-lipoxygenase inhibit expression of intercellular adhesion molecule-1 in human melanoma cells,” Acta Pharmacologica Sinica, vol. 25, no. 5, pp. 672–677, 2004.
[39]
C. Lawson and S. Wolf, “ICAM-1 signaling in endothelial cells,” Pharmacological Reports, vol. 61, no. 1, pp. 22–32, 2009.
[40]
K. B. Reilly, S. Srinivasan, M. E. Hatley et al., “12/15-lipoxygenase activity mediates inflammatory monocyte/endothelial interactions and atherosclerosis in vivo,” The Journal of Biological Chemistry, vol. 279, no. 10, pp. 9440–9450, 2004.