Abstract
Reactive oxygen species (ROS) enhance myocardial ischemia-reperfusion (I/R) injury. Ebselen, a seleno-organic glutathione peroxidase (GPx) mimetic, has a protective effect against tissue injury induced by ROS. However, the cardio-protective effect of orally administered ebselen has never been investigated in cardiac I/R injury. We investigated the effects and mechanisms of orally administered ebselen on experimental myocardial infarction. Isolated perfused rabbit hearts underwent 30 min of global ischemia and 60 min of reperfusion, with or without oral administration of ebselen 24 h before I/R, with or without enhanced oxidative stress by H2O2 infusion for the first 1 min of reperfusion. The recovery of left ventricular developed pressure (LVDP) was significantly improved, and the myocardial infarct size was significantly reduced by ebselen. The recovery of LVDP and the myocardial infarct size were markedly aggravated by H2O2 infusion. These enhancements by H2O2 were dose-dependently suppressed by ebselen, along with a reduction in myocardial 8-hydroxydeoxyguanosine levels, a marker for oxidative DNA damage. The myocardial reduced glutathione (GSH) level was preserved by ebselen. Ebselen markedly enhanced myocardial heat shock protein (HSP) 72 expression. The cardioprotective effect of ebselen-induced HSP72 was confirmed by MTT assay in isolated cardiomyocytes using KNK437, a novel HSP inhibitor. In conclusion, an oral administration of ebselen 24 h before I/R provided excellent cardioprotective effects, at least in part through HSP72 induction and GSH preservation.
Similar content being viewed by others
Article PDF
References
Hozawa A, Ebihara S, Ohmori K, et al: Increased plasma 8-isoprostane levels in hypertensive subjects: the Tsurugaya Project. Hypertens Res 2004; 27: 557–561.
Yasunari K, Maeda K, Nakamura M, Watanabe T, Yoshikawa J : Benidipine, a long-acting calcium channel blocker, inhibits oxidative stress in polymorphonuclear cells in patients with essential hypertension. Hypertens Res 2005; 28: 107–112.
Shimosawa T, Ogihara T, Matsui H, Asano T, Ando K, Fujita T : Deficiency of adrenomedullin induces insulin resistance by increasing oxidative stress. Hypertension 2003; 41: 1080–1085.
Brown JM, Terada LS, Grosso MA, et al: Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic, isolated, perfused rat hearts. J Clin Invest 1988; 81: 1297–1301.
Arteel G, Briviba K, Sies H : Protection against peroxynitrite. FEBS Lett 1999; 445: 226–230.
Lass A, Witting P, Stocker R, Esterbauer H : Inhibition of copper- and peroxyl radical–induced LDL lipid oxidation by ebselen: antioxidant actions in addition to hydroperoxide-reducing activity. Biochim Biophys Acta 1996; 1303: 111–118.
Maiorino M, Roveri A, Coassin M, Ursini F : Kinetic mechanism and substrate specificity of glutathione peroxidase activity of ebselen (PZ 51). Biochem Pharmacol 1988; 37: 2267–2271.
Masumoto H, Kissner R, Koppenol WH, Sies H : Kinetic study of the reaction of ebselen with peroxynitrit. FEBS Lett 1996; 398: 179–182.
Gladilin S, Bidmon HJ, Divanach A, et al: Ebselen lowers plasma interleukin-6 levels and glial heme-oxygenase-1 expression after focal photothrombotic brain ischemia. Arch Biochem Biophys 2000; 380: 237–242.
Kobayashi T, Ohta Y, Yoshino J : Preventive effect of ebselen on acute gastric mucosal lesion development in rats treated with compound 48/80. Eur J Pharmacol 2001; 414: 271–279.
Ozaki M, Nakamura M, Teraoka S, Ota K : Ebselen, a novel antioxidant compound, protects the rat liver from ischemia-reperfusion injury. Transplant Int 1997; 10: 96–102.
Sui H, Wang W, Wang PH, Liu LS : Protective effect of antioxidant ebselen (PZ51) on the cerebral cortex of stroke-prone spontaneously hypertensive rats. Hypertens Res 2005; 28: 249–254.
Hoshida S, Aoki K, Nishida M, et al: Effects of preconditioning with ebselen on glutathione metabolism and stress protein expression. J Pharmacol Exp Ther 1997; 281: 1471–1475.
Morihira M, Hasebe N, Baljinnyam E, et al: Ischemic preconditioning enhances scavenging activity of reactive oxygen species and diminishes transmural difference of infarct size. Am J Physiol Heart Circ 2006; 290: H577–H583.
de Jong JW, van der Meer P, Nieukoop AS, Huizer T, Stroeve RJ, Bos E : Xanthine oxidoreductase activity in perfused hearts of various species, including humans. Circ Res 1990; 67: 770–773.
Downey JM, Miura T, Eddy LJ, et al: Xanthine oxidase is not a sourse of free radicals in the ischemic rabbit heart. J Mol Cell Cardiol 1987; 19: 1053–1060.
Fishbein MC, Meerbaum S, Rit J, et al: Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J 1981; 101: 593–600.
Hasebe N, Shen YT, Kiuchi K, Hittinger L, Bishop SP, Vatner SF : Enhanced postischemic dysfunction selective to subendocardium in conscious dogs with LV hypertrophy. Am J Physiol 1994; 266: H702–H713.
Kaneko T : Formation of 8-oxo-2′-deoxyguanosine in the DNA of human diploid fibroblasts by treatment with linoleic acid hydroperoxide and ferric ion. Lipids 2000; 35: 961–965.
Saito T, Fukuzawa J, Osaki J, et al: Roles of calcineurin and calcium/calmodulin dependent protein kinase II in pressure overload–induced cardiac hypertrophy. J Mol Cell Cardiol 2003; 35: 1153–1160.
Fukuzawa J, Booz GW, Hunt RA, et al: Cardiotropin-1 increases angiotensin mRNA in rat cardiac myocytes through STAT-3. An autocrine loop for hyperthrophy. Hypertension 2000; 35: 1191–1196.
Yokota S, Kitahara M, Nagata K : Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells. Cancer Res 2000; 60: 2942–2948.
Okada M, Hasebe N, Aizawa Y, Izawa K, Kawabe J, Kikuchi K : Thermal treatment attenuates neointimal thickening with enhanced expression of heat-shock protein 72 and suppression of oxidative stress. Circulation 2004; 109: 1763–1768.
Guro V, Hansson G, Dimitresku A, Vaage J : Unstable angina activates myocardial HSP 72, eNOS and transcription factors NFκB and AP-1. Cardiovasc Res 2000; 47: 49–56.
Hutter MM, Sievers RE, Barbosa V, Wolfe CL : Heat shock protein induction in rat hearts. A direct correlation between the amount of heat shock protein induced and the degree of myocardial protection. Circulation 1994; 89: 355–360.
Kukreja RC : Role of KATP channel in heat shock and pharmacological preconditioning. Ann N Y Acad Sci 1999; 30: 211–221.
Kukreja RC, Kontos MC, Loesser KE, et al: Oxidant stress increases heat shock protein 70 mRNA in isolated perfused rat heart. Am J Physiol 1994; 267: H2213–H2219.
Latchman D : Heat shock proteins and cardiac protection. Cardiovasc Res 2001; 51: 637–646.
Okubo S, Wildner O, Maulik RS, Chelliah JC, Hess ML, Kukreja RC : Gene transfer of heat shock protein 70 reduces infarct size in vivo after ischemia/reperfusion in the rabbit heart. Circulation 2001; 103: 877–881.
Blaustein A, Deneke SM, Stolz R, Baxter D, Healey N, Fanburg BL : Myocardial glutathione depletion impairs recovery after short periods of ischemia. Circulation 1989; 80: 1449–1457.
Lapenna D, de Gioia S, Ciofani G, et al: Impaired glutathione biosynthesis in the ischemic-reperfused rabbit myocardium. FEBS Lett 1996; 391: 76–78.
Meister A : Mitochondrial changes associated with glutathione deficiency. Biochim Biophys Acta 1995; 1271: 35–42.
Singh A, Lee K, Lee C, Goldfarb R, Tsan M : Relation between myocardial glutathione content and extent of ischemia-reperfusion injury. Circulation 1989; 80: 1795–1804.
Tritto I, Duilio C, Santoro G, et al: A short burst of oxygen radicals at reflow induces sustained release of oxidized glutathione from postischemic hearts. Free Radic Biol Med 1998; 24: 290–297.
Hoshida S, Kuzuya T, Nishida M, et al: Ebselen protects against ischemia-reperfusion injury in a canine model of myocardial infarction. Am J Physiol 1994; 267: H2342–H2347.
Mulcahy RT, Gipp JJ : Identification of a putative antioxidant response element in the 5′-flanking region of the human gamma-glutamylcysteine synthetase heavy subunit gene. Biochem Biophys Res Commun 1995; 209: 227–233.
Wu A, Moye-Rowley W : GSH1, which encodes gamma-glutamylcysteine synthetase, is a target gene for AP-1 transcriptional regulation. Mol Cell Biol 1994; 14: 5832–5839.
Shaulian E, Karin M : AP-1 as a regulator of cell life and death. Nat Cell Biol 2002; 4: E131–E136.
Hermeniglido C, Nies E, Monsalve E, Puertas F, Higueras V, Romero F : Some aspects of cardiac antioxidant defence: ebselen (PZ51) treatment increases glutathione peroxidase activity in rat heart. Biochem Soc Trans 1990; 18: 1193–1194.
Bolli R, Marban E : Molecular and cellular mechanisms of myocardial stunning. Physiol Rev 1999; 79: 609–634.
Hasebe N, Shen YT, Vatner SF : Inhibition of endothelium-derived relaxing factor enhances myocardial stunning in conscious dogs. Circulation 1993; 88: 2862–2871.
Nagai H, Minatoguchi S, Chen XH, et al: Cilnidipine, an N+L-type dihydropyridine Ca channel blocker, suppresses the occurrence of ischemia/reperfusion arrhythmia in a rabbit model of myocardial infarction. Hypertens Res 2005; 28: 361–368.
Brune B, Diewald B, Ullrich V : Ebselen affects calcium homeostasis in human platelets. Biochem Pharmacol 1991; 41: 1805–1811.
Dimmeler S, Brune B, Ullrich V : Ebselen prevents inositol (1,4,5)-triphoshate binding to its receptor. Biochem Pharmacol 1991; 42: 1151–1153.
Nakagami H, Morishita R, Nishikawa T, et al: Lack of association between the hepatocyte growth factor receptor, c-met, and the anti-apoptotic action of bag-1 in endothelial cells. Hypertens Res 2004; 27: 359–365.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baljinnyam, E., Hasebe, N., Morihira, M. et al. Oral Pretreatment with Ebselen Enhances Heat Shock Protein 72 Expression and Reduces Myocardial Infarct Size. Hypertens Res 29, 905–913 (2006). https://doi.org/10.1291/hypres.29.905
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.29.905
Keywords
This article is cited by
-
Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways
Molecular Biology Reports (2014)
-
Conflicting effects of nitric oxide and oxidative stress in chronic heart failure: potential therapeutic strategies
Heart Failure Reviews (2012)
-
Heat shock transcription factor-1 inhibits H2O2-induced apoptosis via down-regulation of reactive oxygen species in cardiac myocytes
Molecular and Cellular Biochemistry (2011)
-
Lipopolysaccharide pretreatment protects against ischemia/reperfusion injury via increase of HSP70 and inhibition of NF-κB
Cell Stress and Chaperones (2011)
-
Ebselen Improves Ischemia-Reperfusion Injury After Rat Lung Transplantation
Lung (2009)