Abstract
Pharmacological modulation of heme oxygenase (HO) gene expression may have significant therapeutic potential in oxidant-induced disorders, such as ischemia reperfusion (I/R) injury. Higenamine is known to reduce ischemic damages by unknown mechanism(s). The protective effect of higenamine on myocardial I/R-induced injury was investigated. Ligation of rat left anterior descending coronary artery for 30 min under anesthesia was done and followed by 24 h reperfusion before sacrifice. I/R-induced myocardial damages were associated with mitochondria-dependent apoptosis as evidenced by the increase of cytochrome c release and caspase-3 activity. Administration of higenamine (bolus, i.p) 1 h prior to I/R-injury significantly decreased the release of cytochrome c, caspase-3 activity, and Bax expression but up-regulated the expression of Bcl-2, HO-1, and HO enzyme activity in the left ventricles, which were inhibited by ZnPP IX, an enzyme inhibitor of HO-1. In addition, DNA-strand break-, immunohistochemical-analysis, and TUNEL staining also supported the anti-apoptotic effect of higenamine in I/R-injury. Most importantly, administration of ZnPP IX inhibited the beneficial effect of higenamine. Taken together, it is concluded that HO-1 plays a core role for the protective action of higenamine in I/R-induced myocardial injury.
Similar content being viewed by others
Abbreviations
- I/R:
-
ischemia-reperfusion
- Hig:
-
higenamine
- HO-1:
-
heme oxygenase-1
- INF:
-
infarct area
- LAD:
-
left anterior descending coronary artery
- TTC:
-
triphenyltetrazolium chloride
- TUNEL:
-
terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling
- PN:
-
peroxynitrite
- ZnPP IX:
-
zinc protoporphyrin IX
References
Koren G, Weiss AT, Hasin Y, et al (1985) Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Engl J Med 313:1384–1389
Braunwald E, Cannon CP (1995) Hirudin: initial results in acute myocardial infarction, unstable angina and angioplasty. J Am Coll Cardiol 25:30S–37S
Ma XL, Weyrich AS, Lefer DJ, et al (1993) Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to coronary endothelium. Circ Res 72:403–412
Hansen PR (1995) Myocardial reperfusion injury: Experimental evidence and clinical relevance. Eur Heart J 16:734–740
Maulik N, Engelman RM, Rousou JA, et al (1999) Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2. Circulation 100:II369–II375
Kajstura J, Cheng W, Reiss K, et al (1996) Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest 74:86–107
Vulapalli SR, Chen Z, Chua BH, et al (2002) Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis. Am J Physiol Heart Circ Physiol 283:H688–H694.
Fujita T, Toda K, Karimova A, et al (2001) Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis. Nat Med 7:598–604
Tullius SG, Nieminen-Kelha M, Buelow R, et al (2002) Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1. Transplantation 74:591–598
Yet SF, Tian R, Layne MD, et al (2001) Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ Res 89:168–175
Ko YS, Park MK, Kang YJ, et al (2002) Up-regulation of heme oxygenase-1 expression by cAMP-elevating agents in RAW 264.7 cells. J Appl Pharmacol 10:71–77
Kang YJ, Lee YS, Lee GW, et al (1999) Inhibition of activation of nuclear factor kappaB is responsible for inhibition of inducible nitric oxide synthase expression by higenamine, an active component of aconite root. J Pharmacol Exp Ther 291:314–320
Chang KC, Lim JK, Park CW (1986) Synthesis of higenamine and its cardiovascular effects in rabbit: Evidence for β-adrenoceptor agonist. Kor J Pharmacol 22:96–104
Zingarelli B, Salzman AL, Szabo C (1998) Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury. Circ Res 83:85–94
Yamashita N, Hoshida S, Otsu K, et al (1999) Monophosphoryl lipid A provides biphasic cardioprotection against ischemia-reperfusion injury in rat hearts. Br J Pharmacol 128:412–418
Virag L, Szabo C (1999) Inhibition of poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation. Br J Pharmacol 126:769–777
Kahles H, Goring GG, Nordbeck H, et al (1977) Functional behaviour of isolated heart muscle mitochondria after in situ ischemia. Polarographic analysis of mitochondrial oxidative phosphorylation. Basic Res Cardiol 72:563–574
Wu B, Ootani A, Iwakiri R, et al (2004) Ischemic preconditioning attenuates ischemia-reperfusion-induced mucosal apoptosis by inhibiting the mitochondria-dependent pathway in rat small intestine. Am J Physiol Gastrointest Liver Physiol 286:G580–G587
Galang N, Sasaki H, Maulik N (2000) Apoptotic cell death during ischemia/reperfusion and its attenuation by antioxidant therapy. Toxicology 148:111–118
Misao J, Hayakawa Y, Ohno M, et al (1996) Expression of bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation 94:1506–1512
Zhao ZQ, Nakamura M, Wang NP, et al (2000) Reperfusion induces myocardial apoptotic cell death. Cardiovasc Res 45:651–660
Kirshenbaum LA, de Moissac D (1997) The bcl-2 gene product prevents programmed cell death of ventricular myocytes. Circulation 96:1580–1585
Eyssen-Hernandez R, Ladoux A, Frelin C (1996) Differential regulation of cardiac heme oxygenase-1 and vascular endothelial growth factor mRNA expressions by hemin, heavy metals, heat shock and anoxia. FEBS Lett 382:229–233
Csonka, Varga E, Kovacs P, et al (1999) Heme oxygenase and cardiac function in ischemic/reperfused rat hearts. Free Radic Biol Med 27:119–126
Hangaishi M, Ishizaka N, Aizawa T, et al (2000) Induction of heme oxygenase-1 can act protectively against cardiac ischemia/reperfusionin vivo. Biochem Biophys Res Commun 279:582–588
Foresti R, Goatly H, Green CJ, et al (2001) Role of heme oxygenase-1 in hypoxia-reoxygenation: requirement of substrate heme to promote cardioprotection. Am J Physiol Heart Circ Physiol 281:H1976–H1984
Minamino T, Christou H, Hsieh CM, et al (2001) Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci USA 98:8798–8803
Bauer M, Bauer I (2002) Heme oxygenase-1: redox regulation and role in the hepatic response to oxidative stress. Antioxid Redox Signal 4:749–758
Amon M, Menger MD, Vollmar B (2003) Heme oxygenase and nitric oxide synthasemediate cooling-associated protection against TNF-alpha-induced microcirculatory dysfunction and apoptotic cell death. FASEB J 17:175–185
Sato K, Balla J, Otterbein L, et al (2001) Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants. J Immunol 166:4185–4194
Wiesel P, Patel AP, Carvajal IM, et al (2001) Exacerbation of chronic renovascular hypertension and acute renal failure in heme oxygenase-1-deficient mice. Circ Res 88:1088–1094
Bak I, Papp G, Turoczi T, et al (2002) The role of heme oxygenase-related carbon monoxide and ventricular fibrillation in ischemic/reperfused hearts. Free Radic Biol Med 33:639–648
Kim DK, Kim JS, Kim JE, et al (2005) Heme oxygenase-1 induction by dieldrin in dopaminergic cells. Neuroreport 16:509–512
Meffert MK, haley JE, Schuman EM, et al (1994) Inhibition of hippocampal heme oxygenase, nitric oxide synthase, and long-term potentiation by metalloporphyrins. Neuron 13:1225–1235
Appleton SD, Chretien ML, McLaughlin BE, et al (1999) Selective inhibition of heme oxygenase, without inhibition of nitric oxide synthase or soluble guanylyl cyclase, by metalloporphyrins at low concentrations. Drug Metab Dispos 27:1214–1219
Katori M, Buelow R, Ke B, et al (2002) Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway. Transplantation 73:287–292
Blumenthal SB, Kiemer AK, Tiegs G, et al (2005) Metalloporphyrins inactivate caspase-3 and -8. FASEB J 19:1272–1279
Lee YS, Kang YJ, Lee BK, et al (2001) Down-regulation of TNF-a and IL-6 by higenamine is responsible for refunction of infarct size and myocardial ischemic injury in the rat. J Appl Pharmacol 9:167–175
Forbes RA, Steenbergen C, Murphy E (2001) Diazoxide-induced cardioprotection requires signaling through a redox-sensitive mechanism. Circ Res 88:802–809
Cook SA, Sugden PH, Clerk A (1999) Regulation of bcl-2 family proteins during development and in response to oxidative stress in cardiac myocytes: association with changes in mitochondrial membrane potential. Circ Res 85:940–949
von Harndorf R, Li P, Dietz R (1999) Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation 99:2934–2941
Bredesen D (1995) Neural apoptosis. Ann Neurol 38:839–851
Zhang JJ, Chen WW (1985) Protection of the synovial fluid by higenamine. Yao Xue Xue Bao 20:423–426
Brouard S, Otterbein LE, Anrather J, et al (2000) Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 192:1015–1026
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lee, Y.S., Kang, Y.J., Kim, H.J. et al. Higenamine reduces apoptotic cell death by induction of heme oxygenase-1 in rat myocardial ischemia-reperfusion injury. Apoptosis 11, 1091–1100 (2006). https://doi.org/10.1007/s10495-006-7110-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10495-006-7110-y