WO2018130131A1 - miR-342-5p在制备防治心脏病的药物中的应用 - Google Patents

miR-342-5p在制备防治心脏病的药物中的应用 Download PDF

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WO2018130131A1
WO2018130131A1 PCT/CN2018/071807 CN2018071807W WO2018130131A1 WO 2018130131 A1 WO2018130131 A1 WO 2018130131A1 CN 2018071807 W CN2018071807 W CN 2018071807W WO 2018130131 A1 WO2018130131 A1 WO 2018130131A1
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高峰
侯作旭
王立锋
秦兴华
张星
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中国人民解放军第四军医大学
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  • the invention belongs to the technical field of biomedicine and relates to the application of miR-342-5p in preparing medicine for preventing and treating heart disease.
  • Coronary heart disease is the number one killer of human beings, bringing serious medical and economic burdens to society.
  • the main pathological mechanism of coronary heart disease endangering the heart is myocardial ischemia/reperfusion injury after acute coronary occlusion.
  • myocardial ischemia myocardial cell energy metabolism disorder, ATP production decreased, ROS and cytoplasm free Ca 2+ increased; during reperfusion, ROS and cytosolic free Ca 2+ increased further, protease activation, mitochondrial damage aggravated and withered Activation of the death pathway leads to apoptosis and necrosis of cardiomyocytes, affecting cardiac function.
  • a miRNA is a highly conserved non-coding RNA of 19-22 nucleotides in length. It is widely present in the body's cells and degrades the target mRNA or interferes with the target by completely or incompletely pairing with the 3'UTR of the target mRNA. Translation of mRNA. Typically, a miRNA can regulate the expression level or translational capacity of hundreds of mRNAs, and more than 60% of the protein genes are regulated by miRNAs. Therefore, miRNAs play a very important role in post-transcriptional modification of genes, and participate in complex molecular regulation during cell stabilization, adaptation, and pathophysiology.
  • miRNA is an effective target in the prevention and treatment of heart disease.
  • the problem solved by the present invention is to provide the application of miR-342-5p in the preparation of a medicament for preventing and treating heart disease, miR-342-5p protects cardiomyocytes by reducing myocardial ischemia/reperfusion injury, improves cardiac function, and has a heart disease. Medicinal value.
  • miR-342-5p in the preparation of drugs for preventing and treating heart disease.
  • the drug is a drug that has cardioprotective effects and reduces myocardial ischemia/reperfusion injury.
  • the drug is a drug for reducing the levels of caspase9 and JNK2 in cardiomyocytes and reducing apoptosis of cardiomyocytes.
  • the drug is a drug that increases the phosphorylation level of Akt in cardiomyocytes and promotes the survival of cardiomyocytes.
  • miR-342-5p as a target in the preparation of drugs for preventing and treating heart disease.
  • the drug is a drug that regulates its expression at the gene level and/or protein level with miR-342-5p as a drug target.
  • the drug is a drug that synergizes and/or assists miR-342-5p to reduce caspase9 and JNK2 protein levels in cardiomyocytes.
  • the drug synergistically and/or assists miR-342-5p in increasing the phosphorylation level of cardiomyocyte Akt.
  • the drug synergistically and/or assists miR-342-5p in reducing cardiomyocyte apoptosis and promoting cardiomyocyte survival.
  • the present invention has the following beneficial technical effects:
  • miR-342-5p has a significant cardioprotective effect, which can reduce myocardial ischemia/reperfusion injury and improve cardiac function.
  • miR-342-5p is an endogenous substance present in normal cardiomyocytes and has a safety advantage by regulating miR-342-5p to prevent heart disease.
  • miR-342-5p exerts cardioprotective effects by down-regulating apoptosis-related proteins caspase9, JNK2 and activation of cardiomyocyte survival signals, with many targets and good comprehensive effects.
  • Figure 4-1 is a schematic diagram showing the predicted binding sequence of miR-342-5p and related protein mRNA, and the related protein mRNA mutation sequence;
  • miR-342-5p is a miRNA whose sequence is: GAGUUAGUGUCUAUCGUGGGGA.
  • the present invention found that miR-342-5p has a significant cardioprotective effect and can alleviate myocardial ischemia/reperfusion injury, which can be applied to prevent and treat heart disease. Drug.
  • A is the area of myocardial infarction as a percentage of ischemic area
  • miR-342-5p significantly reduced myocardial infarct size and improved cardiac function in SD rats.
  • SD rat cardiomyocytes were isolated by digestion and cultured in DMEM medium containing 10% fetal bovine serum (Sirconia, China) and placed in a 37 ° C incubator (95% Air / 5% CO 2 ). After 48 hours of culture, the cells were changed, and the cells were transfected with LipoiMAX (invitrogen, USA) and miR-342-5p mimic (100 nM). The specific steps were as follows: firstly, 3 ⁇ l of LipoiMAX and 10 ⁇ l of miR-342-5p mimic (20 ⁇ M) and their control NC were separately added to 150 ⁇ l of opti-MEM (invitrogen, USA), and then the two were mixed, and allowed to stand for 5 min and then 1.7.
  • B is the LDH kit to detect the LDH level in the cell culture supernatant, and it can be seen that the LDH is significantly decreased after the addition of miR-342-5p;
  • C is the result of detecting the cell viability of the cck-8 kit, and it can be seen that the cell viability is increased after the addition of miR-342-5p;
  • miR-342-5p significantly reduced hypoxia/reoxygenation injury in neonatal rat cardiomyocytes, which was shown to reduce cardiomyocyte apoptosis and LDH release, and improve cell viability.
  • A is the western result of the apoptosis-related protein
  • miR-342-5p reduced the protein levels of apoptosis-related proteins caspase9 (cleaved caspase9), JNK2 and Bad, and procaspase3 did not change significantly.
  • the Firefly luciferase & Renilla luciferase dual luciferase reporter gene system (constructed by Hanheng Biotechnology Co., Ltd., China) was constructed to analyze the direct effect of miR-342-5p and related protein mRNA in 293T cells.
  • the miR-342-5p and related protein mRNA predicted binding sequences and related protein mRNA mutation sequences are shown in Figure 4-1;
  • miR-342-5p increases the phosphorylation level of cardiomyocyte survival promoting signaling molecule Akt
  • A is the western result of the related protein
  • the results indicate that miR-342-5p increases the phosphorylation level of Akt in the cardiomyocyte survival promoting signaling molecule.
  • miR-342-5p can reduce myocardial ischemia/reperfusion injury and protect cardiomyocytes and improve cardiac function:
  • miR-342-5p can target the apoptosis-related proteins caspase9 and JNK2 mRNA, directly reduce the levels of caspase9 and JNK2 in cardiomyocytes, thereby reducing the levels of activated caspase9 and JNK2 during myocardial ischemia/reperfusion. It inhibits the activation of cardiomyocyte apoptosis signaling pathway and reduces cardiomyocyte apoptosis.
  • miR-342-5p can regulate the survival signal of cardiomyocytes, increase the phosphorylation of Akt, and promote the survival of cardiomyocytes.
  • miR-342-5p can be used as a drug for the prevention and treatment of heart disease.
  • the corresponding miR-342-5p can be used as a target for the preparation of drugs for the prevention and treatment of heart disease.

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Abstract

miR-342-5p在制备防治心脏病的药物中的应用，miR-342-5p具有显著的心脏保护作用，能够减轻心肌缺血/再灌注损伤，改善心脏功能。miR-342-5p是内源性物质，存在于正常的心肌细胞中，通过调节miR-342-5p防治心脏病具有安全性优势。miR-342-5p通过下调细胞凋亡相关蛋白caspase9、JNK2和激活心肌细胞生存信号发挥心脏保护作用，靶点多，综合效果好。

Description

miR-342-5p在制备防治心脏病的药物中的应用 技术领域
本发明属于生物医药技术领域，涉及miR-342-5p在制备防治心脏病的药物中的应用。
背景技术
冠心病是人类的头号杀手，给社会带来严重的医疗和经济负担。而冠心病危害心脏的主要病理机制就是急性冠脉阻塞后发生的心肌缺血/再灌注损伤。在心肌缺血期，心肌细胞能量代谢障碍，ATP生成减少，ROS和细胞浆游离Ca 2+增多；在再灌注期，ROS和细胞浆游离Ca 2+进一步增多，蛋白酶激活，线粒体损伤加重以及凋亡通路激活，导致心肌细胞发生凋亡和坏死，影响心脏功能。目前的介入手术在尽快恢复心肌血供方面发挥了重要作用，但是心肌缺血/再灌注引起的损伤减弱了介入手术的益处，影响了缺血区心肌细胞的存活和心脏功能的恢复。研究减轻心肌缺血/再灌注损伤的方法具有重要的临床意义。
目前干预心肌缺血/再灌注损伤的手段比较有限，常规使用极化液保护心脏。但是极化液在应用中面临越来越多的的挑战，因为冠心病合并糖尿病的患者越来越多，其对存在心肌胰岛素抵抗的患者效果欠佳。因此，寻求新的药物治疗手段已成为世界范围内关注的热点。
miRNA是一类长度在19-22个核苷酸的具有高度保守性的非编码RNA，它广泛存在于机体细胞，通过与靶标mRNA的3’UTR完全或者不完全配对，降解靶标mRNA或者干扰靶标mRNA的翻译。通常，一个miRNA可以调节数百个mRNA的表达水平或翻译能力，并且超过60％的蛋白基因受miRNA的调节。因此，miRNA在基因的转录后修饰中发挥非常重要作用，在细胞稳 态、适应和病理生理过程中参与复杂的分子调控。研究发现，在病理条件下，如心肌缺血，心衰，心肌肥大等，心脏miRNA表达异常，并且，通过干预特定的miRNA可以调节病理过程。因此，miRNA是心脏疾病预防和治疗中的有效靶点。
发明内容
本发明解决的问题在于提供miR-342-5p在制备防治心脏病的药物中的应用，miR-342-5p通过减轻心肌缺血/再灌注损伤保护心肌细胞，改善心脏功能，在心脏病中具有药用价值。
本发明是通过以下技术方案来实现：
miR-342-5p在制备防治心脏病的药物中的应用。
所述的药物是具有心脏保护作用、减轻心肌缺血/再灌注损伤的药物。
所述的药物是降低心肌细胞中caspase9和JNK2蛋白水平，减少心肌细胞凋亡的药物。
所述的药物是增加心肌细胞Akt的磷酸化水平，促进心肌细胞生存的药物。
miR-342-5p作为靶点在制备防治心脏病的药物中的应用。
所述的药物是在基因水平和/或蛋白水平以miR-342-5p作为药物靶点，调节其表达的药物。
所述的药物是协同和/或协助miR-342-5p降低心肌细胞中caspase9和JNK2蛋白水平的药物。
所述的药物协同和/或协助miR-342-5p增加心肌细胞Akt的磷酸化水平的药物。
所述的药物协同和/或协助miR-342-5p减少心肌细胞凋亡、促进心肌细胞生存的药物。
与现有技术相比，本发明具有以下有益的技术效果：
miR-342-5p具有显著的心脏保护作用，能够减轻心肌缺血/再灌注损伤，改善心脏功能。
miR-342-5p是内源性物质，存在于正常的心肌细胞中，通过调节miR-342-5p防治心脏病具有安全性优势。
miR-342-5p通过下调细胞凋亡相关蛋白caspase9、JNK2和激活心肌细胞生存信号发挥心脏保护作用，靶点多，综合效果好。
附图说明
图1为miR-342-5p对在体心脏缺血/再灌注损伤的抑制作用；其中，n＝5，*p＜0.05vs.Pre-I，**p＜0.01vs.I/R；
图2为miR-342-5p对离体心肌细胞缺氧/复氧损伤的抑制作用；其中，n＝4，*p＜0.05；**p＜0.01vs.miR-NC；
图3为miR-342-5p对心肌细胞凋亡相关蛋白的调节；其中，n＝4，*p＜0.05；**p＜0.01vs.mimic-NC，#p＜0.05vs.inhibitor-NC；
图4-1为miR-342-5p与相关蛋白mRNA预测结合序列，以及相关蛋白mRNA突变序列示意图；
图4-2为双荧光素酶报告基因结果；其中，n＝3，**p＜0.01vs.WT-NC；
图5为miR-342-5p对心肌细胞生存信号的调节；其中，n＝3，**p＜0.01vs.mimic-NC，#p＜0.05vs.inhibitor-NC。
具体实施方式
下面结合具体的实施例对本发明做进一步的详细说明，所述是对本发明的解释而不是限定。
miR-342-5p是一种miRNA其序列为：GAGUUAGUGUCUAUCGUGGGGA，本发明通过以下研究发现miR-342-5p具有显著的心脏保护作用，能够减轻心肌缺血/再灌注损伤，其可应用于防治心脏病的药物。
1)miR-342-5p对在体心脏缺血/再灌注(I/R)损伤的抑制
将6周龄雄性SD大鼠随机分为两组，实验组(I/R+miR-342-5p)心肌点注射miR-342-5p agomir(10nmol)，对照组(I/R)心肌点注射其对照试剂。48h后制备心肌缺血再灌注模型。在3％戊巴比妥钠麻醉条件下，结扎大鼠冠状动脉左前降支，30min后松开结扎线进行再灌注2h，用多通道生物信息采集处理系统(AD Instruments，Australia)检测心脏功能并用TTC和伊文氏蓝染色评估心梗面积。
检测结果如图1所示，A为心肌梗死面积占缺血面积百分比，B为心功能指标，两者均反映心肌损伤程度，其中，n＝5，*p＜0.05vs.Pre-I，**p＜0.01vs.I/R。结果表明miR-342-5p显著减少SD大鼠心肌梗死面积，改善心脏功能。
2)miR-342-5p对离体心肌细胞缺氧/复氧损伤的抑制
用消化法分离SD乳鼠心肌细胞，培养在含10％胎牛血清(四季青，中国)的DMEM培养基中，放置于37℃孵箱中(95％Air/5％CO 2)。培养48h后换液，使用LipoiMAX(invitrogen，USA)和miR-342-5p mimic(100nM)转染细胞。具体步骤为：首先将3μl LipoiMAX和10μl miR-342-5p mimic(20μM)及其对照NC分别加入到150μl opti-MEM(invitrogen，USA)中，再将两者混匀，静置5min后与1.7ml含10％胎牛血清(不含抗生素)的DMEM培养基混合，加入细胞中，培养6h后换液，培养48h后进行缺氧(12h)/复氧(3h)刺激，用流式细胞仪检测细胞凋亡，用LDH试剂盒以及cck-8试剂盒检测相关心肌损伤指标。
检测结果如图2所示(其中，n＝4，*p＜0.05；**p＜0.01vs.miR-NC)，A为细胞凋亡百分比的检测结果，其中D为A的原始数据，可以看到加入miR-342-5p后可以减少心肌细胞凋亡；
B为LDH试剂盒检测细胞培养上清中LDH水平，可以看到加入miR-342-5p后LDH显著降低；
C为cck-8试剂盒检测细胞活力的结果，可以看到加入miR-342-5p后细胞活力增加；
综上结果表明miR-342-5p显著减轻乳鼠心肌细胞缺氧/复氧损伤，表现为减少心肌细胞凋亡和LDH释放，提高细胞活力。
3)miR-342-5p对心肌细胞凋亡相关蛋白的调节
使用LipoiMAX和miR-342-5p mimic(100nM)及对照NC，miR-342-5p inhibitor(200nM)及对照NC转染离体SD乳鼠心肌细胞48h后，用western检测相关蛋白水平(包括procaspase3，caspase9，JNK2和Bad)。
如图3所示，A为凋亡相关蛋白的western结果，B为统计结果，其中，n＝4，*p＜0.05；**p＜0.01vs.mimic-NC，#p＜0.05vs.inhibitor-NC。结果表明miR-342-5p降低心肌细胞中凋亡相关蛋白caspase9(procaspase9，cleaved caspase9)，JNK2和Bad的蛋白水平，procaspase3无显著变化。
(4)双荧光素酶报告miR-342-5p与相关蛋白mRNA的作用
构建Firefly luciferase & Renilla luciferase双荧光素酶报告基因系统(委托汉恒生物技术有限公司来构建，中国)，在293T细胞中分析miR-342-5p与相关蛋白mRNA的直接作用。miR-342-5p与相关蛋白mRNA预测结合序列和相关蛋白mRNA突变序列如图4-1所示；
双荧光素酶报告基因结果如图4-2所示，其中，n＝3，**p＜0.01vs.WT-NC。结果表明miR-342-5p直接抑制caspase9和JNK2的mRNA。
5)miR-342-5p增加心肌细胞促生存信号分子Akt的磷酸化水平
使用LipoiMAX和miR-342-5p mimic(100nM)及对照NC，miR-342-5p inhibitor(200nM)及对照NC转染离体SD乳鼠心肌细胞48h后，提取蛋白后western检测相关蛋白的磷酸化水平(包括p-Akt和Akt、p-Erk1/2和Erk1/2)。
如图5所示，A为相关蛋白的western结果，B为统计结果，其中，n＝4， **p＜0.01vs.mimic-NC，#p＜0.05vs.inhibitor-NC。结果表明miR-342-5p增加心肌细胞促生存信号分子Akt的磷酸化水平。
综上实验表明，miR-342-5p能够减轻心肌缺血/再灌注损伤保护心肌细胞、改善心脏功能：
(1)miR-342-5p能够靶向细胞凋亡相关蛋白caspase9和JNK2的mRNA，直接降低心肌细胞中caspase9和JNK2蛋白水平，进而降低心肌细胞缺血/再灌注过程中活化的caspase9和JNK2水平，抑制心肌细胞凋亡信号通路的激活，减少心肌细胞凋亡。
(2)miR-342-5p能够调节心肌细胞生存信号，增加Akt的磷酸化，促进心肌细胞生存。
因此，miR-342-5p能够作为防治心脏病的药物中的应用。
特别是在制备具有心脏保护作用、减轻心肌缺血/再灌注损伤的药物；
在制备降低心肌细胞中caspase9和JNK2蛋白水平，减少心肌细胞凋亡的药物中应用；
以及在制备增加心肌细胞Akt的磷酸化水平，促进心肌细胞生存的药物中应用。
相应的miR-342-5p可以作为靶点用于制备防治心脏病的药物。
特别是在基因水平和/或蛋白水平以miR-342-5p作为药物靶点，调节其表达的药物的制备；
在协同和/或协助miR-342-5p降低心肌细胞中caspase9和JNK2蛋白水平的药物的制备；
在协同和/或协助miR-342-5p增加心肌细胞Akt的磷酸化水平的药物的制备；
以及协同和/或协助miR-342-5p减少心肌细胞凋亡、促进心肌细胞生存的药物的制备。
以上给出的实施例是实现本发明较优的例子，本发明不限于上述实施例。本领域的技术人员根据本发明技术方案的技术特征所做出的任何非本质的添加、替换，均属于本发明的保护范围。

Claims (9)

  1. miR-342-5p在制备防治心脏病的药物中的应用。
  2. 如权利要求1所述的应用，其特征在于，所述的药物是具有心脏保护作用、减轻心肌缺血/再灌注损伤的药物。
  3. 如权利要求1所述的应用，其特征在于，所述的药物是降低心肌细胞中caspase9和JNK2蛋白水平，减少心肌细胞凋亡的药物。
  4. 如权利要求1所述的应用，其特征在于，所述的药物是增加心肌细胞Akt的磷酸化水平，促进心肌细胞生存的药物。
  5. miR-342-5p作为靶点在制备防治心脏病的药物中的应用。
  6. 如权利要求5所述的应用，其特征在于，所述的药物是在基因水平和/或蛋白水平以miR-342-5p作为药物靶点，调节其表达的药物。
  7. 如权利要求5所述的应用，其特征在于，所述的药物是协同和/或协助miR-342-5p降低心肌细胞中caspase9和JNK2蛋白水平的药物。
  8. 如权利要求5所述的应用，其特征在于，所述的药物协是同和/或协助miR-342-5p增加心肌细胞Akt的磷酸化水平的药物。
  9. 如权利要求5所述的应用，其特征在于，所述的药物是协同和/或协助miR-342-5p减少心肌细胞凋亡、促进心肌细胞生存的药物。
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