Browse > Article

Inhibition of Hypoxia-induced Apoptosis in PC12 Cells by Estradiol  

Jung, Ji-Yeon (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Roh, Kwang-Hoon (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Jeong, Yeon-Jin (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Kim, Sun-Hun (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Lee, Eun-Ju (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Kim, Min-Seok (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Oh, Won-Mann (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Oh, Hee-Kyun (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Kim, Won-Jae (Dental Science Research institute, Department of Oral Physiology, School of Dentistry, Chonnam National University)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.9, no.4, 2005 , pp. 231-238 More about this Journal
Abstract
Neuronal apoptotic events, which result in cell death, are occurred in hypoxic/ischemic conditions. Estradiol is a female sex hormone with steroid structure known to provide neuroprotection through multiple mechanisms in the central nervous system. This study was aimed to investigate the signal transduction pathway of $CoCl_2$-induced neuronal cell death and the inhibitory effects of estradiol. Administration of $CoCl_2$ decreased cell viability in both a dose- and time-dependent manner in PC12 cells. $CoCl_2$-induced cell death produced genomic DNA fragmentation and morphologic changes such as cell shrinkage and condensed nuclei. It was found that $CoCl_2$-treated cells increased the reactive oxygen species (ROS) as well as caspase-8, -9 and -3 activities. However, pretreatment with estradiol before exposure to $CoCl_2$ prevented the reduction in cell viability reduction and attenuated DNA fragmentation and morphologic changes caused by $CoCl_2$. Furthermore, the $CoCl_2$-induced increases of ROS levels and caspases activities were attenuated by estradiol. Gene expression analysis revealed that estradiol blocked the underexpression of the Bcl-2 and ameliorated the increase in the release of cytochrome c from mitochondria into cytoplasm and Fas-ligand (Fas-L) upregulated by $CoCl_2$. These results suggest that $CoCl_2$ induce apoptosis in PC12 cells through both mitochondria- and death receptor-mediated cell death pathway. Estradiol was found to have a neuroprotective effect against $CoCl_2$-induced apoptosis through the inhibition of ROS production and by modulating apoptotic effectors associated with the mitochondria- and death-dependent pathway in PC12 cells.
Keywords
Estradiol; Apoptosis; $CoCl_2$; Caspase; Bcl-2 family; Mitochondria;
Citations & Related Records

Times Cited By SCOPUS : 0
연도 인용수 순위
  • Reference
1 Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 281: 1322-1326, 1998   DOI   PUBMED   ScienceOn
2 Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15: 961-973, 1995   DOI   ScienceOn
3 Fleury C, Mignotte B, Vayssiere JL. Mitochondrial reactive oxygen species in cell death signaling. Biochemie 84: 131-141, 2002   DOI   ScienceOn
4 Huang Y, Ray S, Reed JC, Ibrado AM, Tang C, Nawabi A, Bhalla K. Estrogen increases intracellular p26Bcl-2 to p21Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells. Breast Cancer Research and Treatment 42: 73-81, 1997   DOI   ScienceOn
5 Kuida K, Zheng TS, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell RA. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384: 368-372, 1996   DOI   ScienceOn
6 Moosmann, Behl C. The antioxident neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc Natl Acad Sci USA 96: 8867-9972, 1999   DOI
7 Roth JA, Feng L, Walowitz J, Browne RW. Manganese-induced rat pheochromocytoma (PC12) cell death is independent of caspase activation. J Neurosci Res 61: 162-171, 2000   DOI   ScienceOn
8 Wang G, Hazra TK, Mitra S, Lee HM, Englander EW. Mitochondrial DNA damage and a hypoxic response are induced by $CoCl_2$ in rat neuronal PC12 cells. Nucleic Acids Res 28: 2135-2140, 2000   DOI   ScienceOn
9 Xia Z, Lundgren B, Bergstrand A, DePierre JW, Nassberger L. Changes in the generation of reactive oxygen species and in mitochondrial membrane potential during apoptosis induced by the antidepressants imipramine, clomipramine, and citalopram and the effects on these changes by Bcl-2 and Bcl-XL. Biochem Pharm 57: 1199-1208, 1999   DOI   ScienceOn
10 Shen HM, Yang CF, Ding WX, Liu J, Ong CN. Superoxide radical-initiated apoptotic signalling pathway in selenite-treated $HEPG_{2}$ cells: Mitochondria serve as the main target. Free Radical Biology & Medicine 30: 9-21, 2001   DOI   ScienceOn
11 Gottlieb E, Vander Heiden MG, Thompson CB. Bcl-xl prevents the initial decrease in mitochondrial membrane potential and subsequent reactive oxygen species production during tumor necrosis factor alpha-induced apoptosis. Mol Cell Biol 20: 5680-5689, 2000   DOI   ScienceOn
12 Cao YJ, Shibata T, Rainov NG. Hypoxia-inducible transgene expression in differentiated human NT2N neurons-a cell culture model for gene therapy of postischemic neuronal loss. Gene Ther 8: 1357-1362, 2001   DOI   ScienceOn
13 Herrera B, Alvarez AM, Sanchez A, Fernandez M, Roncero C, Benito M, Fabregat I. Reactive oxygen species (ROS) mediates the mitochondrial -dependent apoptosis induced by transforming growth factor (beta) in fetal hepatocytes. FABSE J 15: 741-751, 2001
14 Zou W, Zeng J, Zhuo M, Xu W, Sun L, Wang J, Liu X. Involvement of caspase-3 and p38 mitogen-activated protein kinase in cobalt chloride induced apoptosis in PC12 cells. J Neurosci Res 28: 2135-2140, 2002
15 Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wand X. Cytochrome c and dATP-dependent formation of Aparf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91: 479-489, 1997   DOI   ScienceOn
16 Teixeira C, Reed JC, Pratt MAC. Estrogen promotes hemotherapeutic drug resistance by a mechanism involving Bcl-2 protooncogene expression in human breast cnacer cells. Cancer Res 55: 3902-3907, 1995   PUBMED
17 Crompton M. Mitochondrial intermembrane junctional complexes and their role in cell death. J Physiol 529: 11-21, 2000   DOI   ScienceOn
18 Behl C, Skutella T, Lezoualch F, Post A, Widmann M, Newton CJ, Holsboer F. Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 51: 535-541, 1997   DOI   PUBMED
19 Fujimura M, Morita-Fujimura Y, Murakami K, Kawase M, Chan PH. Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 18: 1239-1247, 1998   DOI   PUBMED
20 Facchinetti F, Furegato S, Terrazzino S, Leon A. $H_{2}O_{2}$ induces upregulation of Fas and Fas ligand expression in NGF-differentiated PC12 cells: Modulation by cAMP. J Neurosci Res 69: 178-188, 2002   DOI   ScienceOn
21 Starkov AA, Polster BM, Fiskum G. Regulation of hydrogen peroxide production by brain mitochondria by calcium and Bax. J Neurochem 83: 220-228, 2002   DOI   ScienceOn
22 Guichun W, Tapas KH, Sankar M, Heung-Man L, Ella WE. Mitochondria DNA damage and a hypoxic condition are induced by $CoCl_{2}$ in rat neuronal PC12 cells. Nucleic Acids Res 28: 2135-2140, 2000   DOI   ScienceOn
23 Krajewski S, Krajewska M, Ellerby LM, welsh K, Xie Z, Deveraux QL. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA 96: 5752-5759, 1999   DOI
24 Green PS, Bishop J, Simpkins JW. 17$\alpha$-Estradiol exerts neuroprotective effects on SK-N-SH cells. J Neurosci Res 17: 511-515, 1997
25 Qin ZH, Wang Y, Kikly KK, Sapp E, Kegel KB, Aroninn N, DiFiglia M. Pro-caspase-8 is predominantly localized in mitochondria and released into cytoplasm upon apoptotic stimulation. J Biol Chem 276: 8079-8086, 2001   DOI   ScienceOn
26 Zhang S, Wang W. Altered expression of Bcl-2 mRNA and Bax in hippocampus with focal cerebral ischemia model in rats. Chin Med J 12: 608-611, 1999
27 Cai J, Jones DP. Superoxide in apoptosis. Mitochondrial generation triggered by cytochrome c loss. J Bio. Chem 273: 11401-11404, 1998   DOI   ScienceOn
28 Kroll SL, Czyzyk-Krzeska MF. Role of $H_{2}O_{2}$ and heme-containing $O_{2}$ sensors in hypoxic regulation of tyrosine hydroxylase gene expression. Am J Physiol 274: 167-174, 1998
29 Singer CA, Rogers KL, Dorsa DM. Modulation of Bcl-2 expression: a potential component of estrogen protection in NT2 neurons. Neuroreport 9: 2565-2568, 1998   DOI   PUBMED   ScienceOn
30 Green PS, Simpkins JW. Neuroprotective effects of estrogen: potential mechanisms of action. Int J Dev Neurosci 18: 347-358, 2000   DOI   ScienceOn
31 Gollapudi L, Oblinger MM. Estrogen and NGF synergistically protect terminally differentiated, ER alpha-transfected PC12 cells from apoptosis. J Neurosci Res 56: 471-481, 1999   DOI   ScienceOn
32 Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci USA 95: 11715-11720, 1998   DOI
33 Howard S, Bottino C, Brooke S, Cheng E, Giffard RG, Sapolsky R. Neuroprotective effects of Bcl-2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage. J Neurochem 83: 914-923, 2002   DOI   ScienceOn
34 Fowthrop DJ, Bloobis AR, Davies DS. Mechanisms of cell death. Arch Toxicol 65: 437-444, 1991   DOI   ScienceOn
35 Zou W, Yan M, Xu W, Huo H, Sun L, Zheng Z, Liu X. Cobalt chloride induces PC12 cells apoptosis through reactive oxygen species and accompanied by AP-1 activation. J Neurosci Res 64: 646-653, 2001   DOI   ScienceOn
36 Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol 63: 29-60, 2001   DOI   ScienceOn
37 Keller JN, Germeyer A, Begley JG, Mattson MP. 17$\beta$-estradiol attenuates oxidative impairment of synaptic Na+/K--ATPase activity, glucose transport, and glutamate transport induced by amyloid beta-peptide and iron. J Neurosci Res 50: 522-530, 1997   DOI   ScienceOn
38 Chae HS, Bach JH, Lee MW, Kim HS, Kim YS, Kim KY, Choo KY, Choi SH, Park CH, Lee SH, Suh YH, Kim SS, Lee WB. Estrogen attenuates cell death induced by carboxy-terminal fragment of amyloid precursor protein in PC12 through a receptor-dependent pathway. J Neurosci Res 65: 403-407, 2001   DOI   ScienceOn
39 Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM. Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 19: 6385-6393, 1999   PUBMED
40 Chandel NS, Schumacker PT. Cells depleted of mitochondrial DNA (rho0) yield insight into physiological mechanisms. FEBS Lett 454: 173-176, 1999   DOI   PUBMED   ScienceOn
41 Tsujimoto Y, Shimizu S. Bcl-2: Life-or-death switch. FEBS Lett 466: 6-10, 2000   DOI   ScienceOn
42 Hosoda T, Nakajima H, Honjo H. Estrogen protects neuronal cells from amyloid beta-induced apoptotic cell death. Neuroreport 12: 1965-1970, 2001   DOI   ScienceOn
43 Green PS, Gridley KE, Simpkins JW. Estradiol protects against beta-amyloid (25-35) induced toxicity in SK-N-SH human neuroblastoma cells. Neuroscience Lett 218: 165-168, 1996   DOI   ScienceOn
44 Shimizu S, Eguchi Y, Kamiike W, Matsuda H, Tsujimoto Y. Bcl-2 expression prevents activation of the ICE protease cascade. Oncogene 12: 2251-2257, 1996   PUBMED