HIF-1对H9c2心肌细胞新基因Mipu1表达的影响及其机制研究
摘要
缺氧诱导因子-1(hypoxia-inducible factor-1,HIF-1)是调节与缺氧反应相关基因表达的最重要作用的转录因子。HIF-1由组成型表达的α和β两个亚单位构成,其α亚单位(HIF-1α)为HIF-1的活性亚基和调节亚基。研究表明,采用氯化钴(cobalt chloride,CoCl_2)诱导或HIF-1α基因转染等使HIF-1α表达上调的方法可保护心肌免于缺血或缺血/再灌注(ischemia/reperfusion,I/R)引起的损伤。并且越来越多的证据表明,HIF-1参与了缺血预适应(ischemic preconditioning,IP)对心肌的保护作用。HIF-1调节心肌细胞在缺血/再灌注过程生存的机制目前还不十分清楚,可能与其激活心肌保护相关基因的表达有关。Mipul是我室采用大鼠心肌缺血预适应动物模型筛选到的一个新基因,命名为心肌缺血预适应表达上调蛋白(Myocardial ischemic preconditioning upregulated protein 1,Mipul,又名Znf667),该基因是一个锌指型核转录抑制因子。采用生物信息学分析发现,在Mipul的启动子区含有一个HIF-1保守的缺氧反应元件(hypoxia response element,HRE),提示HIF-1可能是Mipul的上游调控因子。本研究旨在首次探讨HIF-1对新基因Mipul表达的影响并揭示其可能的调控机制。
本课题以大鼠胚胎心脏来源的H9c2心肌细胞为研究对象,将H9c2细胞随机分成5个组:(1)对照组(Ctrl):以PBS(phosphate buffersolution)处理细胞;(2)CoCl_2组(Co):以200μmol/L CoCl_2处理细胞12h;(3)空载体组(Neo):以pEF-BOS空载体瞬时转染细胞;(4)HIF-1α过表达组(HIF):以表达人HIF-1α全长的质粒pEF-BOS-HIF-1α瞬时转染细胞;(5)HIF-1α过表达加CoCl_2组(HIF+Co):HIF-1α过表达质粒瞬时转染,同时以200μmol/L CoCl_2处理细胞12h。采用逆转录-聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)观察H9c2细胞HIF-1αmRNA的表达情况;进一步的机制研究,采用间接免疫荧光技术观察HIF-1α蛋白在H9c2细胞的分布及表达情况;然后以RT-PCR和Western Blot观察HIF-1α表达上调对Mipul表达的影响;采用荧光素酶报告基因检测HIF-1α表达上调对Mipul启动子转录活性的影响;采用凝胶电泳迁移率分析(electrophoreticmobility shift assays,EMSA)及supershift观察HIF-1是否与Mipul启动子区的HRE直接结合。
结果显示:
(1)CoCl_2组HIF-1αmRNA水平没有明显变化(p＞0.05 vs Ctrl),HIF-1α过表达组HIF-1αmRNA水平明显增高(p＜0.05 vs Neo),HIF-1α过表达加CoCl_2组HIF-1αmRNA的水平没有明显变化(p＞0.05 vsHIF);
(2)对照组HIF-1α蛋白分布于H9c2细胞的胞浆及胞核。CoCl_2组、HIF-1α过表达组及两者联合处理组细胞内HIF-1α蛋白的表达均明显增多,并且由细胞浆向细胞核移位;
(3)CoCl_2组和HIF-1α过表达组Mipul mRNA和蛋白的表达均明显增高(p＜0.05,Co vs Ctrl;p＜0.05,HIF vs Neo),HIF-1α过表达加CoCl_2组Mipul的表达没有明显变化(p＞0.05 vs HIF);
(4)CoCl_2组和HIF-1α过表达组Mipul启动子的转录活性均明显增高(p＜0.01,Co vs Ctrl;p＜0.01,HIF vs Neo),HIF-1α过表达加CoCl_2组的Mipul启动子的转录活性没有明显变化(p＞0.05 vs HIF);
(5)HIF-1可直接与Mipul启动子区的HRE结合。
综上所述,可得出如下结论:(1)HIF-1通过与Mipul启动子区的HRE结合促进H9c2细胞Mipul的表达;(2)CoCl_2通过诱导HIF-1α的蛋白表达促进H9c2细胞Mipul的表达。
Hypoxia-inducible factor-1(HIF-1) is the principal transcription factor involves in the regulation of gene expression in response to hypoxia.HIF-1 is a heterodimer comprised ofαandβsubunits,which are constitutively expressed.Theαsubunit is the activated and regulatory subunit of HIF-1.Some researches showed that up-regulated expression of HIF-1αby cobalt chloride(CoCl_2) treatment or transfecting HIF-1αgene confered cardioprotection against ischemic or ischemia/reperfusion (I/R) injury.More and more evidence suggested that HIF-1 was involved in cardioprotection induced by ischemic preconditioning(IP).The specific mechanism by which HIF-1 regulates cell survival in I/R is still unclear,but it likely involves multiple pathways that activate genes related to cardioprotection.Mipu1(myocardial ischemic preconditioning up- regulated protein 1),also known as Znf667,is a novel gene which was found to be up-regulated in rat heart after myocardial ischemic preconditioning in our laboratory.It served as a zinc finger nuclear transcription inhibitor.Bioinformatics analysis showed that a consensus hypoxia response element(HRE) of HIF-1 was found in the promoter of Mipu1.It indicated that HIF-1 may be the upstream regulator of Mipu1. This study was attempted to explore the effect of HIF-1 on the expression of the novel gene Mipu1 and its mechanism.
In this study,The embryonic rat heart-derived cell line H9c2 cardiomyocytes were divided into five groups:(1) control group(Ctrl): H9c2 cells treated with PBS(Sphosphate buffer solution);(2) CoCl_2 group(Co):H9c2 cells treated with 200μmol/L CoCl_2 for 12h;(3) empty vector group(Neo):H9c2 cells transfected with pEF-BOS empty vector; (4) over-expressed HIF-1αgroup(HIF):H9c2 cells transfected with human HIF-1αfull-length plasmid(pEF-BOS-HIF-1α);(5) over -expressed HIF-1αplus CoCl_2 group(HIF+Co):H9c2 cells transfected with pEF-BOS-HIF-1αand treated with 200μmol/L CoCl_2 for 12h.Then reverse transcription-polymerase chain reaction(RT-PCR) was used to observe the expression of HIF-1αmRNA.Indirectly Immunofluorescence was used to observe the expression of HIF-1αprotien and its distribution in H9c2 cells.RT-PCR and Western Blot were used to observe the effect of HIF-1αon Mipu1 expression in H9c2 cells.Luciferase reporter gene was used to observe the effect of HIF-1αon the transcriptional activity of Mipu1 promoter.EMSA(Electrophoretic Mobility Shift Assays) and supershift was used to observe whether HIF-1 could bind to HRE of Mipu1 promoter.
The results showed that:
(1) The expression of H/F-1αmRNA did not change in CoCl_2 group (p＞0.05,vs Ctrl).However,it increased significantly in over-expressed HIF-1αgroup(p＜0.05 vs Neo).And the expression of HIF-1αmRNA did not change in over-expressed HIF-1αplus CoCl_2 group(p＞0.05 vs HIF).
(2) HIF-1αprotein located in cytoplasm and nucleus of H9c2 cells in control group.The expression of HIF-1αprotein increased significantly and HIF-1αtranslocated from cytoplasm to nucleus in CoCl_2 group, over-expressed HIF-1αgroup and over-expressed HIF-1αplus CoCl_2 group.
(3) The expression of Mipu1 mRNA and protein increased significantly in CoCl_2 group and over-expressed HIF-1αgroup(p＜0.05, Co vs Ctrl;p＜0.05,HIF vs Neo).However,it did not change in over-expressed HIF-1αplus CoCl_2 group(p＞0.05,vs HIF).
(4) The transcriptional activity of Mipu1 promoter increased significantly in CoCl_2 group and over-expressed HIF-1αgroup(p＜0.01, Co vs Ctrl;p＜0.01,HIF vs Neo).However,it did not change in over-expressed HIF-1αplus CoCl_2 group(p＞0.05,vs HIF).
(5) HIF-1 could bind to HRE of Mipu1 promoter.
In conclusion,(1) HIF-1 promoted expression of Mipu1 in H9c2 cells through binding to HRE of Mipu1 promoter.(2) CoCl_2 promoted expression of Mipu1 in H9c2 cells through inducing expression of HIF-1αprotein.
本课题以大鼠胚胎心脏来源的H9c2心肌细胞为研究对象,将H9c2细胞随机分成5个组:(1)对照组(Ctrl):以PBS(phosphate buffersolution)处理细胞;(2)CoCl_2组(Co):以200μmol/L CoCl_2处理细胞12h;(3)空载体组(Neo):以pEF-BOS空载体瞬时转染细胞;(4)HIF-1α过表达组(HIF):以表达人HIF-1α全长的质粒pEF-BOS-HIF-1α瞬时转染细胞;(5)HIF-1α过表达加CoCl_2组(HIF+Co):HIF-1α过表达质粒瞬时转染,同时以200μmol/L CoCl_2处理细胞12h。采用逆转录-聚合酶链反应(reverse transcription-polymerase chain reaction,RT-PCR)观察H9c2细胞HIF-1αmRNA的表达情况;进一步的机制研究,采用间接免疫荧光技术观察HIF-1α蛋白在H9c2细胞的分布及表达情况;然后以RT-PCR和Western Blot观察HIF-1α表达上调对Mipul表达的影响;采用荧光素酶报告基因检测HIF-1α表达上调对Mipul启动子转录活性的影响;采用凝胶电泳迁移率分析(electrophoreticmobility shift assays,EMSA)及supershift观察HIF-1是否与Mipul启动子区的HRE直接结合。
结果显示:
(1)CoCl_2组HIF-1αmRNA水平没有明显变化(p＞0.05 vs Ctrl),HIF-1α过表达组HIF-1αmRNA水平明显增高(p＜0.05 vs Neo),HIF-1α过表达加CoCl_2组HIF-1αmRNA的水平没有明显变化(p＞0.05 vsHIF);
(2)对照组HIF-1α蛋白分布于H9c2细胞的胞浆及胞核。CoCl_2组、HIF-1α过表达组及两者联合处理组细胞内HIF-1α蛋白的表达均明显增多,并且由细胞浆向细胞核移位;
(3)CoCl_2组和HIF-1α过表达组Mipul mRNA和蛋白的表达均明显增高(p＜0.05,Co vs Ctrl;p＜0.05,HIF vs Neo),HIF-1α过表达加CoCl_2组Mipul的表达没有明显变化(p＞0.05 vs HIF);
(4)CoCl_2组和HIF-1α过表达组Mipul启动子的转录活性均明显增高(p＜0.01,Co vs Ctrl;p＜0.01,HIF vs Neo),HIF-1α过表达加CoCl_2组的Mipul启动子的转录活性没有明显变化(p＞0.05 vs HIF);
(5)HIF-1可直接与Mipul启动子区的HRE结合。
综上所述,可得出如下结论:(1)HIF-1通过与Mipul启动子区的HRE结合促进H9c2细胞Mipul的表达;(2)CoCl_2通过诱导HIF-1α的蛋白表达促进H9c2细胞Mipul的表达。
Hypoxia-inducible factor-1(HIF-1) is the principal transcription factor involves in the regulation of gene expression in response to hypoxia.HIF-1 is a heterodimer comprised ofαandβsubunits,which are constitutively expressed.Theαsubunit is the activated and regulatory subunit of HIF-1.Some researches showed that up-regulated expression of HIF-1αby cobalt chloride(CoCl_2) treatment or transfecting HIF-1αgene confered cardioprotection against ischemic or ischemia/reperfusion (I/R) injury.More and more evidence suggested that HIF-1 was involved in cardioprotection induced by ischemic preconditioning(IP).The specific mechanism by which HIF-1 regulates cell survival in I/R is still unclear,but it likely involves multiple pathways that activate genes related to cardioprotection.Mipu1(myocardial ischemic preconditioning up- regulated protein 1),also known as Znf667,is a novel gene which was found to be up-regulated in rat heart after myocardial ischemic preconditioning in our laboratory.It served as a zinc finger nuclear transcription inhibitor.Bioinformatics analysis showed that a consensus hypoxia response element(HRE) of HIF-1 was found in the promoter of Mipu1.It indicated that HIF-1 may be the upstream regulator of Mipu1. This study was attempted to explore the effect of HIF-1 on the expression of the novel gene Mipu1 and its mechanism.
In this study,The embryonic rat heart-derived cell line H9c2 cardiomyocytes were divided into five groups:(1) control group(Ctrl): H9c2 cells treated with PBS(Sphosphate buffer solution);(2) CoCl_2 group(Co):H9c2 cells treated with 200μmol/L CoCl_2 for 12h;(3) empty vector group(Neo):H9c2 cells transfected with pEF-BOS empty vector; (4) over-expressed HIF-1αgroup(HIF):H9c2 cells transfected with human HIF-1αfull-length plasmid(pEF-BOS-HIF-1α);(5) over -expressed HIF-1αplus CoCl_2 group(HIF+Co):H9c2 cells transfected with pEF-BOS-HIF-1αand treated with 200μmol/L CoCl_2 for 12h.Then reverse transcription-polymerase chain reaction(RT-PCR) was used to observe the expression of HIF-1αmRNA.Indirectly Immunofluorescence was used to observe the expression of HIF-1αprotien and its distribution in H9c2 cells.RT-PCR and Western Blot were used to observe the effect of HIF-1αon Mipu1 expression in H9c2 cells.Luciferase reporter gene was used to observe the effect of HIF-1αon the transcriptional activity of Mipu1 promoter.EMSA(Electrophoretic Mobility Shift Assays) and supershift was used to observe whether HIF-1 could bind to HRE of Mipu1 promoter.
The results showed that:
(1) The expression of H/F-1αmRNA did not change in CoCl_2 group (p＞0.05,vs Ctrl).However,it increased significantly in over-expressed HIF-1αgroup(p＜0.05 vs Neo).And the expression of HIF-1αmRNA did not change in over-expressed HIF-1αplus CoCl_2 group(p＞0.05 vs HIF).
(2) HIF-1αprotein located in cytoplasm and nucleus of H9c2 cells in control group.The expression of HIF-1αprotein increased significantly and HIF-1αtranslocated from cytoplasm to nucleus in CoCl_2 group, over-expressed HIF-1αgroup and over-expressed HIF-1αplus CoCl_2 group.
(3) The expression of Mipu1 mRNA and protein increased significantly in CoCl_2 group and over-expressed HIF-1αgroup(p＜0.05, Co vs Ctrl;p＜0.05,HIF vs Neo).However,it did not change in over-expressed HIF-1αplus CoCl_2 group(p＞0.05,vs HIF).
(4) The transcriptional activity of Mipu1 promoter increased significantly in CoCl_2 group and over-expressed HIF-1αgroup(p＜0.01, Co vs Ctrl;p＜0.01,HIF vs Neo).However,it did not change in over-expressed HIF-1αplus CoCl_2 group(p＞0.05,vs HIF).
(5) HIF-1 could bind to HRE of Mipu1 promoter.
In conclusion,(1) HIF-1 promoted expression of Mipu1 in H9c2 cells through binding to HRE of Mipu1 promoter.(2) CoCl_2 promoted expression of Mipu1 in H9c2 cells through inducing expression of HIF-1αprotein.
引文
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[2]Wang G L,J iang B H,Rue E A,et al.Hypoxia-inducible factor 1 is a basic helix-loop-helix-PAS heterodimer regulated by cellular O_2 tension[J].Proc Natl Acad Sci USA,1995,92(12):5510-14.
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[10] Kido M ,Du L, Sullivan CC, et al.Hypoxia inducible factor -1alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse[J].J Am Coll Cardiol,2005,46 (11): 2116-2124
[11] Jianhua Fengl, Eliana Lucchinetti, Michael Zaugg Cardiac remodelling hinders activation of cyclooxygenase-2, diminishing protection by delayed pharmacological preconditioning: role of HIF1a and CREB[J]. Cardiovasc Res,2008,78,98-107
[12] Blanco Pamp in J, Garcia Rivero SA, O tero Cepeda XL, et al.Immunohistochemical expression of HIF-1 alpha in response to early myocardial ischemia[J].J Forensic Sci, 2006, 51 (1): 120-124
[13] Alina Maloyan,1 Luba Eli-Berchoer Gregg L. Semenza, HIF-1-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart[J].Physiol Genomics, 2005,23: 79-88.
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[1]Murry CE,Jennings RB,Reimer KA.Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocardium[J].Circulation 1986,74:1124-1136.
[2]Wang G L,J iang B H,Rue E A,et al.Hypoxia-inducible factor 1 is a basic helix-loop-helix-PAS heterodimer regulated by cellular O_2 tension[J].Proc Natl Acad Sci USA,1995,92(12):5510-14.
[3]Lee J W,Bae S H,Jeong J W,et al.Hypoxia-inducible factor(HIF-1) alpha:its protein stability and biological functions[J].Exp Mol Med,2004,36(1):1-12.
[4]Kallio PJ,Wilson WJ,O Brien S,et al.Regulation of the hypoxia-inducible transcription factor 1α by the ubiquitin-proteasome pathway[J].J Biol Chem 1999,274:6519-25
[5]Mei Yee Koh,Taly R.Spivak-Kroizman,et al.HIF-1 regulation:not so easy come,easy go.2008 Elsevier Ltd.doi:10.1016/j.tibs.2008.08.002 Trends in Biochemical Sciences Vol.33 No.11
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[7] Patty J. Lee, Bing-Hua Jiang, Beek Yoke, et al.Hypoxia-inducible Factor-1 Mediates Transcriptional Activation of the Heme Oxygenase-1 Gene in Response to Hypoxia[J]. J Biol Chem 1997,272: 5375-5381.
[8] Jung F, Palmer LA, Zhou N, Johns RA,et al.Hypoxic regulation of inducible nitric oxide synthase via hypoxia inducible factor-1 in cardiac myocytes[J]. Circ Res 2000,86:319-25
[9] Semenza G L,Wang GL. A nuclear factor induced by hypoxia via denovo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation [J]. Mol Cell Biol, 1992,12 (12): 5447-54.
[10] Kido M ,Du L, Sullivan CC, et al.Hypoxia inducible factor -1alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse[J].J Am Coll Cardiol,2005,46 (11): 2116-2124
[11] Jianhua Fengl, Eliana Lucchinetti, Michael Zaugg Cardiac remodelling hinders activation of cyclooxygenase-2, diminishing protection by delayed pharmacological preconditioning: role of HIF1a and CREB[J]. Cardiovasc Res,2008,78,98-107
[12] Blanco Pamp in J, Garcia Rivero SA, O tero Cepeda XL, et al.Immunohistochemical expression of HIF-1 alpha in response to early myocardial ischemia[J].J Forensic Sci, 2006, 51 (1): 120-124
[13] Alina Maloyan,1 Luba Eli-Berchoer Gregg L. Semenza, HIF-1-targeted pathways are activated by heat acclimation and contribute to acclimation-ischemic cross-tolerance in the heart[J].Physiol Genomics, 2005,23: 79-88.
[14] Natarajan R, Salloum FN , Fisher BJ , et al. Hypoxia inducible Factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury [J]. Circ Res ,2006 ,98 (1) :133-140.
[15] Parsa CJ, Kim J, Riel RU, et al. Cardioprotective effects of EPO in the reperfused ischemic heart: a potential role for cardiac fibroblasts[J]. J Biol Chem,2004,279: 20655-20662.
[16] Moon C, Krawczyk M,Ahn D, et al. Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats [ J ].Proc Natl Acad Sci USA, 2003, 100 (20): 11612-11617.
[17] Hirata A,Minamino T, Asanuma H, et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs[J]. J Am Coll Cardiol, 2006, 48 (1):176-184.
[18] Calvillo L, Latini R, Kajstura J, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling [J]. Proc Natl Acad Sci USA, 2003,100 (8): 4802-4806.
[19] Wu H,Lee SH, Gao J , et al. Inactivation of erythropoietin leads to defects in cardiac morphogenesis[J]. Development, 1999,126 (16): 3597-3605.
[20] Baxter GF. The neutrophil as a mediator of myocardial ischemia-reperfusion injury: time to move on. Basic Res Cardiol 2002,97: 268-275.
[21] Liu X, Xie W, L iu P, et al. Mechanism of the cardioprotection of rhEPO pretreatment on suppressing the inflammatory response in ischemia-reperfusion [J]. Life Sci, 2006,78 (19): 2255-2264.
[22] Rafiee P, Shi Y, Su J , et al. Erythropoietin protects the infant heart against ischemia-reperfusion injury by triggering multiple signaling pathways [J]. Basic Res Cardiol, 2005, 100 (3): 187-197.
[23] SilvaM, Benito A, Sanz C, et al. Erythropoietin can induce the expression of bcl2x (L) through Stat5 in erythropoietin-dependent progenitor cell lines[J]. J Biol Chem, 1999, 274: 22165-22169.
[24] Rui T, Feng Q, LeiM, et al. Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1[J]. Cardiovasc Res, 2005, 65 (3):719-727.
[25] Xi L , Taher M , Yin C. Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1 alpha and AP-1 and iNOS signaling [J]. Am J Physiol Heart Circ Physiol ,2004 ,287:2369-2375.
[26] Xi L, Jarrett NC, Hess ML, and Kukreja RC. Myocardial ischemia/reperfusion injury in the inducible nitric oxide synthase knockout mice[J].Life Sci 1999,65: 935-945.
[27] Xi L ,Tekin D ,Gursoy E , et al . Evidence that NOS acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia[J]. Am J Physiol Heart Circ Physiol ,2002 ,283 (1) :H5 - 12.
[28] Jugdutt BI. Nitric oxide and cardiovascular protection[J].Heart Fail Rev,2003,8 (1):29-34.
[29] Llorens S Jordan J ,Nava E. The nitric oxide pathway in the cardiovascular system[J]. J Physiol Biochem,2002 ,58 (3):179 - 188.
[30] Razavi HM, Hamilton JA, Feng Q. Modulation of apoptosis by nitric oxide: implications in myocardial ischemia and heart failure[J]. Pharmacol Ther 2005;106(2):147-162
[31] Mateo J, Garcia-Lecea M, Cadenas S, et al.Regulation of hypoxia-inducible factor-1 by nitric oxide through mitochondria-dependent and -independent pathways[J]. J Bio chem, 2003,376:537-544.
[32] Poon BY, Raharjo E, Patel KD, et al. Complexity of inducible nitric oxide synthase: cellular source determines benefit versus toxicity[J].Circulation,2003,108:1107-1112.
[33] FerraraN.Molecular and biological properties of vascular endothelial growth factor[J]. J Mol Med, 1999, 77 (7): 43.
[34] Spyridopoulos I , Brogi E , Kearney M, et al .VEGF inhibits endothelial cell apoptosis induced by tumor necrosis factor-α: balance between growth and death signals [J]. J Mol Cell Cardiol, 1997 , 29 :1 321 - 330
[35] Liu LX ,Lu H ,Luo Y,et al. Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1[J].Biochem Biophys Res Commun ,2002 ,291:908-914.
[36] Ng I, Tan WL ,Ng PY,et al. Hypoxia inducible factor-1alpha and expression of vascular endothelial growth factor and its receptors in cerebral arteriovenous malformations [J]. J Clin Neurosci ,2005 ,12 :794-799.
[37] Hojo Y, Ikeda U, Zhu Y, et al . Expression of VEGF in patients with acute myocardial infarction [J]. J Am Coll Cardiol, 2000, 35 :968 - 973
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