MCP-1相关miRNAs在大鼠脑出血后继发性脑损伤中的作用及机制的初步研究
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摘要
背景：
脑出血(ICH)是严重危害人类健康的疾病,影响脑出血预后的关键因素是继发性脑损伤,现认为其与多种细胞内信号表达异常相关,而microRNA可在多个层面调控细胞内信号通路。我们前期的研究发现MCP-1/CCR2通路可介导ICH后继发性脑损伤,本研究拟在前期研究的基础上,进一步探讨MCP-l相关的miRNAs在大鼠脑出血中的表达及其与ICH后继发性脑损伤的关系。
材料与方法：
本研究通过生物信息学技术预测可能靶向MCP-1mRNA分子,并在大鼠脑出血模型上进行了初步的筛选试验。总共81只雄性SD大鼠被随机分为3组：假手术组(针刺基底节模型)、对照组(生理盐水基底节注射模型)和处理组(自体血基底节注射模型),在模型建立后2小时(h),6小时(h),12小时(h)后断头取脑,采集标本后提取RNA,通过qRT-PCR技术检测MCP-1mRNA以及相应microRNA分子表达水平差异并分析其相关性。
结果：
ICH后MCP-1基因相对表达量升高,3h为29.44±0.18,6h为73.84±1.16,12h为125.86±15.31,同时,rno-miR-3592相对表达量为3h20.58±0.64,6h16.06±0.98,12h15.24±1.29,rno-miR-434*相对表达量为3h20.58±0.64,6h16.08±0.98,12h15.24±1.29。相关性分析显示在大鼠[CH模型中,rno-miR-3592和rno-miR-434*与MCP-1表达强相关。
结论：
我们的研究描述了在大鼠脑出血早期,血肿周围脑组织中MCP-1mRNA及相应miRNA分子的动态变化。其中rno-miR-3592.rno-miR-434*分子在脑出血早期呈现进行性下降趋势,而同期脑组织内MCP-mRNA表达水平呈进行性上升趋势,由此我物推测rno-miR-3592,mo-miR-434*分子可能参与调控了MCP-1介导的脑出血后继发性脑损伤机制。而rno-miR-3592,rno-miR-434*对MCP-1信号通路的作用及调控机制有待进一步研究证实。
Background
Intracerebral hemorrhage(ICH) is a common and fatal subtype of stroke.The key role affecting the prognosis of ICH is secondary brain injury. Extensive research has demonstrated that ICH triggers complex cellular biochemical events that eventually lead to secondary brain injury. However, the delicate mechanisms of ICH induced secondary brain injury are not completely understood. MicroRNAs have been recently discovered as a novel family of non-protein coding short RNA molecules that negatively modulte protein expression in virous organisms.It is now evident that miRNAs plays acritical role in a ariety of normal biological process, including cell differentiation, apoptosis, development and metabolism. In addition, miRNAs have also been implicated in etiology of variety of human disease, including cancer, cardiovascular diseases and stroke. Our previous study have demonstrated that CCL2/CCR2pathway play an important role in the secondary brain injury after ICH. Based on these data, this study is to investigate the expression of MCP-1related miRNAs in a rat ICH model and elucidate the role of miRNAs in the pathogenesis of the ICH induced secondary brain injury.
Methods
In this study, we predict possible targeting MCP-1mRNA by bioinformatics techniques,and a preliminary screening test was carried out in a rat ICH model.A total of81rats were randomly divided into3groups:sham group(acupuncture basal ganglia model),control group(saline basal ganglia injection model)and treat group(autologous blood basal ganglia injection model).Rats were decapitated and collected brain sample2hours,6hours,12hours after respectively. Total RNA was isolated from rat brain samples,and the expression of MCP-1mRNA and miRNAs were measured by real-time PCR.
Results
The expression of MCP-1mRNA increased significantly after ICH, which was29.44±0.18at3h,73.84±1.16at6h and25.86±15.31at12h, respectively. At the same time, the expression of rno-miR-3592was20.58±0.64at3h,16.06±0.98at6h,and15.24±1.29at12h, respectively. The expression of rno-miR-434*was20.58±0.64at3h,16.08±0.98at6h, and15.24±1.29at12h, respectively. Correlation analysis revealed that rno-miR-3592and rno-miR-434*are strongly correlated with the expression of MCP-1mRNA.
Conclusion
Our study describes the dynamic changes of MCP-1mRNA and the related miRNA in the brain tissue around hematoma at early stage after ICH.rno-miR-3592,rno-miR-434*showed progressive decrease when MCP-1mRNA expression levels showed a progressive upward trend. Thus, we speculate that rno-miR-3592and rno-miR-434*may modulate the expression of MCP-1expression in ICH. However, futher studies are needed to elucidate the effect and mechanisms of rno-miR-3592and rno-miR-434*on MCP-1signaling pathway in ICH induced secondary brain injury following ICH.
脑出血(ICH)是严重危害人类健康的疾病,影响脑出血预后的关键因素是继发性脑损伤,现认为其与多种细胞内信号表达异常相关,而microRNA可在多个层面调控细胞内信号通路。我们前期的研究发现MCP-1/CCR2通路可介导ICH后继发性脑损伤,本研究拟在前期研究的基础上,进一步探讨MCP-l相关的miRNAs在大鼠脑出血中的表达及其与ICH后继发性脑损伤的关系。
材料与方法：
本研究通过生物信息学技术预测可能靶向MCP-1mRNA分子,并在大鼠脑出血模型上进行了初步的筛选试验。总共81只雄性SD大鼠被随机分为3组：假手术组(针刺基底节模型)、对照组(生理盐水基底节注射模型)和处理组(自体血基底节注射模型),在模型建立后2小时(h),6小时(h),12小时(h)后断头取脑,采集标本后提取RNA,通过qRT-PCR技术检测MCP-1mRNA以及相应microRNA分子表达水平差异并分析其相关性。
结果：
ICH后MCP-1基因相对表达量升高,3h为29.44±0.18,6h为73.84±1.16,12h为125.86±15.31,同时,rno-miR-3592相对表达量为3h20.58±0.64,6h16.06±0.98,12h15.24±1.29,rno-miR-434*相对表达量为3h20.58±0.64,6h16.08±0.98,12h15.24±1.29。相关性分析显示在大鼠[CH模型中,rno-miR-3592和rno-miR-434*与MCP-1表达强相关。
结论：
我们的研究描述了在大鼠脑出血早期,血肿周围脑组织中MCP-1mRNA及相应miRNA分子的动态变化。其中rno-miR-3592.rno-miR-434*分子在脑出血早期呈现进行性下降趋势,而同期脑组织内MCP-mRNA表达水平呈进行性上升趋势,由此我物推测rno-miR-3592,mo-miR-434*分子可能参与调控了MCP-1介导的脑出血后继发性脑损伤机制。而rno-miR-3592,rno-miR-434*对MCP-1信号通路的作用及调控机制有待进一步研究证实。
Background
Intracerebral hemorrhage(ICH) is a common and fatal subtype of stroke.The key role affecting the prognosis of ICH is secondary brain injury. Extensive research has demonstrated that ICH triggers complex cellular biochemical events that eventually lead to secondary brain injury. However, the delicate mechanisms of ICH induced secondary brain injury are not completely understood. MicroRNAs have been recently discovered as a novel family of non-protein coding short RNA molecules that negatively modulte protein expression in virous organisms.It is now evident that miRNAs plays acritical role in a ariety of normal biological process, including cell differentiation, apoptosis, development and metabolism. In addition, miRNAs have also been implicated in etiology of variety of human disease, including cancer, cardiovascular diseases and stroke. Our previous study have demonstrated that CCL2/CCR2pathway play an important role in the secondary brain injury after ICH. Based on these data, this study is to investigate the expression of MCP-1related miRNAs in a rat ICH model and elucidate the role of miRNAs in the pathogenesis of the ICH induced secondary brain injury.
Methods
In this study, we predict possible targeting MCP-1mRNA by bioinformatics techniques,and a preliminary screening test was carried out in a rat ICH model.A total of81rats were randomly divided into3groups:sham group(acupuncture basal ganglia model),control group(saline basal ganglia injection model)and treat group(autologous blood basal ganglia injection model).Rats were decapitated and collected brain sample2hours,6hours,12hours after respectively. Total RNA was isolated from rat brain samples,and the expression of MCP-1mRNA and miRNAs were measured by real-time PCR.
Results
The expression of MCP-1mRNA increased significantly after ICH, which was29.44±0.18at3h,73.84±1.16at6h and25.86±15.31at12h, respectively. At the same time, the expression of rno-miR-3592was20.58±0.64at3h,16.06±0.98at6h,and15.24±1.29at12h, respectively. The expression of rno-miR-434*was20.58±0.64at3h,16.08±0.98at6h, and15.24±1.29at12h, respectively. Correlation analysis revealed that rno-miR-3592and rno-miR-434*are strongly correlated with the expression of MCP-1mRNA.
Conclusion
Our study describes the dynamic changes of MCP-1mRNA and the related miRNA in the brain tissue around hematoma at early stage after ICH.rno-miR-3592,rno-miR-434*showed progressive decrease when MCP-1mRNA expression levels showed a progressive upward trend. Thus, we speculate that rno-miR-3592and rno-miR-434*may modulate the expression of MCP-1expression in ICH. However, futher studies are needed to elucidate the effect and mechanisms of rno-miR-3592and rno-miR-434*on MCP-1signaling pathway in ICH induced secondary brain injury following ICH.
引文
[1]中华人民共和国卫生部.2010年中国卫生统计年鉴,北京,中国协和医科大学出版社,2010
[2]Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke.2011 Jun;42(6):1781-1786
[3]Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet.2009 May 9;373(9675):1632-44.
[4]Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol.2010 Dec;92(4):463-477.
[5]Conductier G, Blondeau N, Guyon A, Nahon JL, Rovere C. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol.2010 Jul 27;224(1-2):93-100.
[6]Bartel DP. MicroRNAs:target regognition and regulatory fuctions. Cell.2009 Jan 23;136(2):215-213.
[7]Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature.2011 Jan 20;469(7330):336-42.
[8]Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature.2010 Aug 12;466(7308):835-40.
[9][9]Liu DZ, Tian Y, Ander BP, Xu H, Stamova BS, Zhan X, et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab.2010 Jan;30(1):92-101.
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[2]Aronowski J, Zhao X. Molecular pathophysiology of cerebral hemorrhage: secondary brain injury. Stroke.2011 Jun;42(6):1781-1786
[3]Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet.2009 May 9;373(9675):1632-44.
[4]Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol.2010 Dec;92(4):463-477.
[5]Conductier G, Blondeau N, Guyon A, Nahon JL, Rovere C. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol.2010 Jul 27;224(1-2):93-100.
[6]Bartel DP. MicroRNAs:target regognition and regulatory fuctions. Cell.2009 Jan 23;136(2):215-213.
[7]Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature.2011 Jan 20;469(7330):336-42.
[8]Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature.2010 Aug 12;466(7308):835-40.
[9][9]Liu DZ, Tian Y, Ander BP, Xu H, Stamova BS, Zhan X, et al. Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab.2010 Jan;30(1):92-101.
[10]Tan JR, Koo YX, Kaur P, Liu F, Armugam A, Wong PTH, Jeyaseelan K. MicroRNA in stroke pathogenesis. Curr Mol Med.2011;11(2):76-92.
[11]Xi G, Wagner KR, Keep RF, et al. Role of blood clot formation on early edema development after experimental intracerebral hemorrhage. Stroke,2000,29(12): 2580-2586.
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