Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23404
標題: 異丙酚降低大鼠新生心肌細胞受艾黴素影響導致經粒線體的細胞凋亡
Propofol Ameliorates Doxorubicin-induced Mitochondrion-mediated Cellular Apoptosis in Rat Neonatal Cardiomyocytes
作者: 王麗娟
Wang, Li-Chuan
關鍵字: Propofol;異丙酚;Doxorubicin;Cardiomyocytes;Apoptosis;Mitochondrion;艾黴素;心肌細胞;細胞凋亡;粒線體
出版社: 生命科學院碩士在職專班
引用: 第十章 參考文獻 ALLAOUCHICHE, B., R. DEBON, J. GOUDABLE, D. CHASSARD and F. DUFLO, 2001 Oxidative stress status during exposure to propofol, sevoflurane and desflurane. Anesth Analg 93: 981-985. ARBEL, N., and V. SHOSHAN-BARMATZ, 2009 Voltage-dependent anion channel-1-based peptides interact with Bcl2 to prevent anti-apoptotic activity. J Biol Chem. BAKER, M. T., and M. NAGUIB, 2005 Propofol: the challenges of formulation. Anesthesiology 103: 860-876. BERNUZZI, F., S. RECALCATI, A. ALBERGHINI and G. CAIRO, 2009 Reactive oxygen species-independent apoptosis in doxorubicin-treated H9c2 cardiomyocytes: role for heme oxygenase-1 down-modulation. Chem Biol Interact 177: 12-20. BRADFORD, M. M., 1976 A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254. BUDIHARDJO, I., H. OLIVER, M. LUTTER, X. LUO and X. WANG, 1999 Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15: 269-290. BURLACU, A., 2003 Regulation of apoptosis by Bcl-2 family proteins. J Cell Mol Med 7: 249-257. CARMICHAEL, J., W. G. DEGRAFF, A. F. GAZDAR, J. D. MINNA and J. B. MITCHELL, 1987 Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47: 936-942. CHAISWING, L., M. P. COLE, D. K. ST CLAIR, W. ITTARAT, L. I. SZWEDA et al., 2004 Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury. Toxicol Pathol 32: 536-547. CHANDRA, J., A. SAMALI and S. ORRENIUS, 2000 Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 29: 323-333. CHILDS, A. C., S. L. PHANEUF, A. J. DIRKS, T. PHILLIPS and C. LEEUWENBURGH, 2002 Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res 62: 4592-4598. DEEPA, P. R., and P. VARALAKSHMI, 2006 Influence of a low-molecular-weight heparin derivative on the nitric oxide levels and apoptotic DNA damage in adriamycin-induced cardiac and renal toxicity. Toxicology 217: 176-183. DESAGHER, S., and J. C. MARTINOU, 2000 Mitochondria as the central control point of apoptosis. Trends Cell Biol 10: 369-377. FAN, T. J., L. H. HAN, R. S. CONG and J. LIANG, 2005 Caspase family proteases and apoptosis. Acta Biochim Biophys Sin (Shanghai) 37: 719-727. GAVRIELI, Y., Y. SHERMAN and S. A. BEN-SASSON, 1992 Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119: 493-501. GEAR, A. R., 1974 Rhodamine 6G. A potent inhibitor of mitochondrial oxidative phosphorylation. J Biol Chem 249: 3628-3637. GREEN, P. S., and C. LEEUWENBURGH, 2002 Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis. Biochim Biophys Acta 1588: 94-101. GRINER, E. M., and M. G. KAZANIETZ, 2007 Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7: 281-294. HALESTRAP, A. P., S. J. CLARKE and S. A. JAVADOV, 2004 Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. Cardiovasc Res 61: 372-385. HENGARTNER, M. O., and J. A. BRYANT, 2000 Apoptotic cell death: from worms to wombats ... but what about the weeds? Symp Soc Exp Biol 52: 1-12. IIJIMA, T., T. MISHIMA, K. AKAGAWA and Y. IWAO, 2006 Neuroprotective effect of propofol on necrosis and apoptosis following oxygen-glucose deprivation--relationship between mitochondrial membrane potential and mode of death. Brain Res 1099: 25-32. INOGUCHI, T., T. SONTA, H. TSUBOUCHI, T. ETOH, M. KAKIMOTO et al., 2003 Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase. J Am Soc Nephrol 14: S227-232. JAVADOV, S. A., K. H. LIM, P. M. KERR, M. S. SULEIMAN, G. D. ANGELINI et al., 2000 Protection of hearts from reperfusion injury by propofol is associated with inhibition of the mitochondrial permeability transition. Cardiovasc Res 45: 360-369. JEONG, S. Y., and D. W. SEOL, 2008 The role of mitochondria in apoptosis. BMB Rep 41: 11-22. JIN, Y. C., W. KIM, Y. M. HA, I. W. SHIN, J. T. SOHN et al., 2009 Propofol limits rat myocardial ischemia and reperfusion injury with an associated reduction in apoptotic cell death in vivo. Vascul Pharmacol 50: 71-77. KARASHIMA, Y., M. OIKE, S. TAKAHASHI and Y. ITO, 2002 Propofol prevents endothelial dysfunction induced by glucose overload. Br J Pharmacol 137: 683-691. KIM, H. S., W. C. CHANG, K. C. HWANG, I. G. CHOI and W. K. PARK, 2008 Effect of propofol on calcium homeostasis in hypoxia-reoxygenated neonatal rat cardiomyocytes. Eur J Pharmacol 594: 139-145. KO, S. H., C. W. YU, S. K. LEE, H. CHOE, M. J. CHUNG et al., 1997 Propofol attenuates ischemia-reperfusion injury in the isolated rat heart. Anesth Analg 85: 719-724. LE BRAS, M., M. V. CLEMENT, S. PERVAIZ and C. BRENNER, 2005 Reactive oxygen species and the mitochondrial signaling pathway of cell death. Histol Histopathol 20: 205-219. LEE, S. J., D. C. KIM, B. H. CHOI, H. HA and K. T. KIM, 2006 Regulation of p53 by activated protein kinase C-delta during nitric oxide-induced dopaminergic cell death. J Biol Chem 281: 2215-2224. LIU, B., Y. CHEN and D. K. ST CLAIR, 2008a ROS and p53: a versatile partnership. Free Radic Biol Med 44: 1529-1535. LIU, K. X., T. RINNE, W. HE, F. WANG and Z. XIA, 2007 Propofol attenuates intestinal mucosa injury induced by intestinal ischemia-reperfusion in the rat. Can J Anaesth 54: 366-374. LIU, T. J., Y. C. YEH, C. T. TING, W. L. LEE, L. C. WANG et al., 2008b Ginkgo biloba extract 761 reduces doxorubicin-induced apoptotic damage in rat hearts and neonatal cardiomyocytes. Cardiovasc Res 80: 227-235. LIU, Z., X. D. SONG, Y. XIN, X. J. WANG, H. YU et al., 2009 Protective effect of chrysoeriol against doxorubicin-induced cardiotoxicity in vitro. Chin Med J (Engl) 122: 2652-2656. LUO, T., Z. XIA, D. M. ANSLEY, J. OUYANG, D. J. GRANVILLE et al., 2005 Propofol dose-dependently reduces tumor necrosis factor-alpha-Induced human umbilical vein endothelial cell apoptosis: effects on Bcl-2 and Bax expression and nitric oxide generation. Anesth Analg 100: 1653-1659. MACFARLANE, M., and A. C. WILLIAMS, 2004 Apoptosis and disease: a life or death decision. EMBO Rep 5: 674-678. MAJUMDER, P. K., N. C. MISHRA, X. SUN, A. BHARTI, S. KHARBANDA et al., 2001 Targeting of protein kinase C delta to mitochondria in the oxidative stress response. Cell Growth Differ 12: 465-470. MAMMOTO, T., M. MUKAI, A. MAMMOTO, Y. YAMANAKA, Y. HAYASHI et al., 2002 Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Lett 184: 165-170. MATHY-HARTERT, M., G. DEBY-DUPONT, P. HANS, C. DEBY and M. LAMY, 1998 Protective activity of propofol, Diprivan and intralipid against active oxygen species. Mediators Inflamm 7: 327-333. MCDERMOTT, B. J., S. MCWILLIAMS, K. SMYTH, E. J. KELSO, J. P. SPIERS et al., 2007 Protection of cardiomyocyte function by propofol during simulated ischemia is associated with a direct action to reduce pro-oxidant activity. J Mol Cell Cardiol 42: 600-608. MURPHY, E., K. IMAHASHI and C. STEENBERGEN, 2005 Bcl-2 regulation of mitochondrial energetics. Trends Cardiovasc Med 15: 283-290. NAGATA, S., 2000 Apoptotic DNA fragmentation. Exp Cell Res 256: 12-18. OTT, M., V. GOGVADZE, S. ORRENIUS and B. ZHIVOTOVSKY, 2007 Mitochondria, oxidative stress and cell death. Apoptosis 12: 913-922. PANARETAKIS, T., E. LAANE, K. POKROVSKAJA, A. C. BJORKLUND, A. MOUSTAKAS et al., 2005 Doxorubicin requires the sequential activation of caspase-2, protein kinase Cdelta, and c-Jun NH2-terminal kinase to induce apoptosis. Mol Biol Cell 16: 3821-3831. RAGAB, A. H., W. W. SUTOW, D. M. KOMP, K. A. STARLING, G. M. LYON, JR. et al., 1975 Adriamycin in the treatment of childhood solid tumors. A Southwest Oncology Group study. Cancer 36: 1567-1576. REYLAND, M. E., 2007 Protein kinase Cdelta and apoptosis. Biochem Soc Trans 35: 1001-1004. SIDDIQUI, R. A., M. ZEROUGA, M. WU, A. CASTILLO, K. HARVEY et al., 2005 Anticancer properties of propofol-docosahexaenoate and propofol-eicosapentaenoate on breast cancer cells. Breast Cancer Res 7: R645-654. SIMUNEK, T., M. STERBA, O. POPELOVA, M. ADAMCOVA, R. HRDINA et al., 2009 Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep 61: 154-171. SINGAL, P. K., T. LI, D. KUMAR, I. DANELISEN and N. ILISKOVIC, 2000 Adriamycin-induced heart failure: mechanism and modulation. Mol Cell Biochem 207: 77-86. SKARKA, L., and B. OSTADAL, 2002 Mitochondrial membrane potential in cardiac myocytes. Physiol Res 51: 425-434. SPALLAROSSA, P., S. GARIBALDI, P. ALTIERI, P. FABBI, V. MANCA et al., 2004 Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol 37: 837-846. STEPHAN, H., H. SONNTAG, H. D. SCHENK and S. KOHLHAUSEN, 1987 [Effect of Disoprivan (propofol) on the circulation and oxygen consumption of the brain and CO2 reactivity of brain vessels in the human]. Anaesthesist 36: 60-65. TAKEMURA, G., and H. FUJIWARA, 2007 Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog Cardiovasc Dis 49: 330-352. TSUCHIYA, M., A. ASADA, E. KASAHARA, E. F. SATO, M. SHINDO et al., 2002 Antioxidant protection of propofol and its recycling in erythrocyte membranes. Am J Respir Crit Care Med 165: 54-60. VANLERSBERGHE, C., and F. CAMU, 2008 Propofol. Handb Exp Pharmacol: 227-252. WANG, B., J. SHRAVAH, H. LUO, K. RAEDSCHELDERS, D. D. CHEN et al., 2009a Propofol protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via Akt activation and Bcl-2 up-regulation. Biochem Biophys Res Commun 389: 105-111. WANG, H., Z. XUE, Q. WANG, X. FENG and Z. SHEN, 2008 Propofol protects hepatic L02 cells from hydrogen peroxide-induced apoptosis via activation of extracellular signal-regulated kinases pathway. Anesth Analg 107: 534-540. WANG, H. Y., G. L. WANG, Y. H. YU and Y. WANG, 2009b The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats. Brain Res 1297: 177-184. WANG, J., X. YANG, C. V. CAMPORESI, Z. YANG, G. BOSCO et al., 2002 Propofol reduces infarct size and striatal dopamine accumulation following transient middle cerebral artery occlusion: a microdialysis study. Eur J Pharmacol 452: 303-308. WILSON, J. X., and A. W. GELB, 2002 Free radicals, antioxidants, and neurologic injury: possible relationship to cerebral protection by anesthetics. J Neurosurg Anesthesiol 14: 66-79. WU, X. J., Y. J. ZHENG, Y. Y. CUI, L. ZHU, Y. LU et al., 2007 Propofol attenuates oxidative stress-induced PC12 cell injury via p38 MAP kinase dependent pathway. Acta Pharmacol Sin 28: 1123-1128. XU, J. J., and Y. L. WANG, 2008 Propofol attenuation of hydrogen peroxide-mediated oxidative stress and apoptosis in cultured cardiomyocytes involves haeme oxygenase-1. Eur J Anaesthesiol 25: 395-402. YEH, Y. C., H. C. LAI, C. T. TING, W. L. LEE, L. C. WANG et al., 2007 Protection by doxycycline against doxorubicin-induced oxidative stress and apoptosis in mouse testes. Biochem Pharmacol 74: 969-980. YOSHIDA, K., 2007 PKCdelta signaling: mechanisms of DNA damage response and apoptosis. Cell Signal 19: 892-901. ZHAO, K., G. LUO, S. GIANNELLI and H. H. SZETO, 2005 Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell lines. Biochem Pharmacol 70: 1796-1806. ZHOU, S., L. J. HELLER and K. B. WALLACE, 2001 Interference with calcium-dependent mitochondrial bioenergetics in cardiac myocytes isolated from doxorubicin-treated rats. Toxicol Appl Pharmacol 175: 60-67.
摘要: 
在臨床上,異丙酚是一種靜脈注射藥劑作為全身麻醉手術使用。近幾年來的基礎生物醫學研究也發現,低濃度的異丙酚能對保護心臟對抗氧化壓力及細胞凋亡的能力。因其酚環化學結構類似維生素E所以具有清除自由基已產生抗氧化壓力的功能,但是對於其抗心肌細胞凋亡的分子機制仍待釐清。艾黴素為一種抗癌藥劑,在臨床及實驗動物研究都發現艾黴素會造成氧化傷害及引起的心臟功能降低。所以,本論文以初級培養的新生大鼠心肌細胞處理艾黴素以誘發產生細胞凋亡,作為探討異丙酚是否能對抗心肌細胞凋亡,以及其可能的保護機制是否經由粒線體路徑產生抗氧化作用。初級培養新生大鼠心肌細胞的處理有控制組、異丙酚 (1μM)組、艾黴素 (1μM)組和異丙酚加艾黴素組 (細胞培養液中加入異丙酚一小時後加入艾黴素)。心肌細胞以艾黴素處理二十四小時後,發現心肌細胞存活率下降、誘發凋亡細胞死亡、破壞Bcl-2家族蛋白質平衡、破壞粒線體膜電位、加速依粒線體的凋亡訊息、增加p53和蛋白質激酶-δ裂解蛋白的表現、減少超氧歧化脢 (SOD)和穀胱甘肽過氧化酶 (GPx)表現、活化caspase-3活性,然而,心肌細胞前處理異丙酚能有效防止艾黴素這些不良的氧化和前凋亡的作用。另外,前處理rhodamine 6G去抑制心肌細胞依粒線體的功能,證實了異丙酚無法改變其增加的p53、蛋白質激酶-δ裂解蛋白和細胞凋亡。這些發現提供異丙酚具有有效和廣泛對抗的能力來對抗艾黴素經由依粒線體細胞凋亡路徑的細胞毒性的證據,也提升了異丙酚在臨床上的應用,有希望減弱艾黴素對心臟影響的輔助藥劑。

Clinically, 2,6-diisopropylphenol (propofol) is commonly used as an intravenous agent for general anesthia. Recent basic biomedical researches also found that low dose of profol could protect hearts against oxidative stress and apoptosis. The antioxidant mechanism of propofol is manily related to its phenolic chemical structure similar to phenol-based free radical scavenging activity such as vitamin E, however, the possible role of propofol on molecular mechanism of apoptosis in cardiomyocytes is still to be clarified. Doxorubicin, one of the potent anti-cancer agents, induce oxidative stress and apoptosis have been reported to provoke cardiac dysfunction via clinical and experimental studies. In this study, we were interested in whether the protective mechanisms of propofol against doxorubicin induce-neonatal rat cardiomyocytes apoptosis were related to its antioxidative effects via mitochondrial-dependent pathways. Primary cultured neontal rat cardiomyocytes were treated with vehicle, propofol (1 μM), doxorubicin (1 μM), or propofol plus doxorubicin (post-treatment with doxorubicin 1 h after propofol). After 24 h, cells administrated with doxorubicin displayed reduced viability of cardiomyocytes, induced apoptotic cell death, disturbed Bcl-2 family protein balance, disrupted mitochondrial membrane potential, precipitated mitochondrion-dependent apoptotic signalling, upregulated p53 and PKC-δ-cleaved protein expression, downergulated superoxidate dismutase and glutathione peroxidase expressions, and activated caspase-3 activity, whereas pretreatment of propofol could effectively prevent these entire undesirable oxidative and proapoptotic actions of doxorubicin. Additionally, pretreatment of rhodamine 6G (R6G) to inhibit the mitochondrial-dependent function of cardiomyocytes confirmed that increased levels of p53, PKC-δ-cleaved proteins and apoptosis could not be converted by propofol. In conclusion, these findings provided evidences that propofol possess potent and extensive counteracting capability against doxorubicin cardiotoxicity via mitochondrial-dependent apoptotic pathways, and raise propofol to be a promising adjuvant agent that may antagonize the untoward cardiac effects of doxorubicin in clinical application.
URI: http://hdl.handle.net/11455/23404
其他識別: U0005-0302201014161000
Appears in Collections:生命科學系所

Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.