CN111494400A - miRNA-483-3p在调控自发性高血压大鼠血压、心脏及血管方面的作用 - Google Patents
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Abstract
本发明涉及miRNA‑483‑3p在调控自发性高血压大鼠血压、心脏及血管方面的作用。它能使自发性高血压大鼠的收缩压、舒张压、平均动脉压都能保持在初始范围内而不再持续升高;它能使心脏射血分数和左室短轴缩短率明显升高,心脏重量指数下降,从而明显改善心脏结构和功能;它能使腹主动脉胶原纤维减少,内膜明显变薄,管腔变宽,内皮细胞排列整齐,从而使腹主动脉结构、厚度、内膜完整性得到不同程度的改善。因此,本发明所揭示的miRNA‑483‑3p可作为高血压治疗的新靶点。
Description
技术领域
本发明涉及microRNA(miRNA)在调控高血压方面的应用,具体涉及miRNA-483-3p在调控自发性高血压大鼠血压、心脏及血管方面的作用。
背景技术
高血压是我国最常见的心血管疾病,可导致多种严重并发症,如慢性心力衰竭、慢性肾功能衰竭、脑中风等。高血压病因和发病机制复杂,涉及多种效应器官和靶器官。目前临床推荐使用的抗高血压药物有六大类:利尿剂、钙拮抗剂、β受体拮抗剂、α1受体拮抗剂、血管紧张素转换酶抑制剂、血管紧张素Ⅱ受体拮抗剂。这些药物以控制血压,预防并发症为主,尚不能达到根治效果。
高血压病因和发病机制不清是制约高血压疗效的核心因素。近年来研究发现,miRNA与心血管疾病密切相关。miRNA是一类来源于内源性发夹结构转录本的长度大约为18~22个核苷酸的内源性小分子非编码单链RNA,通过与靶mRNA的3’非翻译区特异性结合,促进靶mRNA降解,或者抑制靶mRNA翻译,降低编码蛋白质水平,从而实现对基因转录后的表达调控。miRNA的调控既有特异性(如根据碱基配对原则调控靶基因,导致其转录翻译受阻等),同时由于其碱基序列相对较少,以碱基配对原则所调控的基因相对多(哺乳动物miRNA每个可能调控约200个靶基因),所以从miRNA角度理解和研究复杂性系统性疾病显得更为契合实际。有报道发现高血压发病与miRNA的调控关系密切,如miRNA-221等,调控高血压发病过程中炎症反应状态。在高血压发病过程中也发现多个miRNA(如miRNA-29,miRNA505,miRNA-126等)出现表达异常,降压治疗后其又恢复到原来的水平。可见,miRNA与高血压发病关系密切。
专利(CN201210069224.9)发现miRNA-21能有效降低自发性高血压大鼠的血压水平,同时改善了心脏功能。专利(CN200880109703.0)发现miRNA-29a-c具有抗心脏组织中纤维化作用。但未见miRNA-483-3p在调控自发性高血压大鼠血压、心脏及血管方面作用的报道。
发明内容
本发明提供了miRNA-483-3p 在调控自发性高血压大鼠血压、心脏及血管方面作用的技术方案:
1本发明技术特征在于从尾静脉注射miR-483-3p sponge后,自发性高血压大鼠的血压能够保持在初始范围内而不再持续升高,心脏结构和功能得到明显改善,腹主动脉结构、厚度、内膜完整性得到不同程度的改善。
2如上所述的血压能够保持在初始范围内,其特征在于自发性高血压大鼠的收缩压、舒张压、平均动脉压都能保持在初始范围内,而不再持续升高。
3如上所述的心脏结构和功能得到明显改善,其特征在于射血分数(EjectionFraction,EF)、左室短轴缩短率(Fractional Shortening,FS)明显升高,心脏重量指数(Heart Weight Index, HWI)下降。
4如上所述的腹主动脉结构、厚度、内膜完整性得到不同程度的改善,其特征在于大鼠腹主动脉胶原纤维减少,内膜明显变薄,管腔变宽,内皮细胞排列整齐,内膜结构趋于正常。
有益效果
1 本发明揭示了miRNA-483-3p能有效抑制自发性高血压大鼠的血压的升高趋势,使之保持在初始范围内而不再持续升高,为临床治疗高血压提供了药靶。
2 本发明揭示了miRNA-483-3p能明显升高EF和FS,降低心脏重量指数,从而改善了心脏的结构和功能。
3 本发明揭示了miRNA-483-3p能减少大鼠腹主动脉的胶原纤维,降低内膜厚度,缩小管腔,使内皮细胞排列整齐,从而改善了腹主动脉结构、厚度、内膜完整性。
附图说明
图1为收缩压变化图
图2为舒张压变化图
图3为平均动脉压变化图
图4为EF图
图5为FS图
图6为HWI图
图7为wistar组HE染色图
图8为SHR组HE染色图
图9为NC组HE染色图
图10为miRNA-483-3p组HE染色图
图11为wistar组Masson染色图
图12为SHR组Masson染色图
图13为NC组Masson染色图
图14为miRNA-483-3p组Masson染色图
实验例
本发明通过以下实施例对miRNA-483-3p (略写为miR-483-3p,下同)在调控自发性高血压大鼠血压、心脏及血管方面的作用进行详细说明,但不是全部的实施例。基于本发明中的实施例,本领域技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明的保护范围。
实施例1 miR-483-3p对自发性高血压(Spontaneously Hypertensive Rats,SHR)大鼠血压的作用
1 大鼠分组
健康SPF级Wistar,SHR雄性大鼠32只,体重200±20g,置于SPF级实验室中饲养,自由活动,自由进食、饮水,通风,光照充足,室温控制在(25±1)℃,相对湿度70%-80%,适应性饲养7天后进行实验。SHR大鼠按基础血压法随机分为3组,即SHR组、SHR+NC组、SHR+mir-483-3p组,每组8只。
尾静脉注射方法
(1)SHR+NC组尾静脉注射HBAAV2/9-GFP NC对照空表达载体干预(滴度:1.6*1012TU/ml,162.5ul),SHR+miR-483-3p组尾静脉注射HBAAV2/9-rno-mir-483-3p-sponge-GFP(滴度:1.3*1012TU/ml,200µL)腺病毒表达载体干预,Wistar和SHR组尾静脉注射等容积生理盐水,注射结束后饲养10周。
(2)自尾静脉注射结束后,对大鼠进行体重称量,每两周一次血压测量,连续10周,结果见附图1-3。
由附图1-3知,第0周血压监测表明,wistar大鼠与SHR大鼠的血压比较有显著性差异;尾静脉注射后,第4周起至第10周血压测量发现,与wistar组比较,SHR组和NC组大鼠收缩压、舒张压、平均动脉压明显升高(p<0.05),与SHR组和NC组比较,miR-483-3p组大鼠收缩压、舒张压、平均动脉压基本保持在正常范围内(p<0.05)。
实施例2 miR-483-3p对SHR大鼠心脏结构和功能的作用
动物分组及给药方式同实施例1。
实验结束时,采用小动物超声检测EF ,FS和 HWI,结果见附图4-6。
由附图4-6知,超声心动图测定大鼠心功能:与wistar组大鼠相比,NC和SHR组大鼠EF和FS明显下降(p<0.05),与NC和SHR组大鼠相比,miR-483-3p组大鼠的EF和FS明显升高(p<0.05)。此外,与wistar大鼠比较,SHR和NC组大鼠HWI明显升高(p<0.05),与SHR和NC组大鼠比较,miR-483-3p组大鼠HWI下降(p<0.05)。
实施例3 miR-483-3p对SHR大鼠腹主动脉结构的作用
动物分组及给药方式同实施例1。
实验结束后,用异氟醚麻醉大鼠并使其牺牲,剥离心脏并称重,计算心脏重量指数(心脏重量/胫骨长度之比(mg/mm))。取出心脏组织心尖部位,在液氮中冷冻,-80℃保存至后续实验。其余用4%多聚甲醛固定进行病理分析,嵌入石蜡进行常规组织学处理,准备4μm切片,HE 染色观察炎症细胞浸润、心肌坏死情况附图7-10;Masson 染色分析心肌纤维化程度,结果见附图11-14。
由附图7-10知,大鼠腹主动脉HE染色下表现:Wistar组动脉内膜结构正常,无增厚,表面光滑,内皮连续完整无突起。SHR和NC组大鼠动脉内膜明显增厚,管腔变窄,内膜结构紊乱,内皮细胞排列不完整。miR-483-3p组大鼠腹主动脉结构、厚度、内膜完整性均较SHR和NC组有不同程度改善。
由附图11-14知,大鼠腹主动脉Masson染色下表现:与Wistar组比较,SHR和NC组大鼠胶原纤维增多。与SHR和NC组比较,miR-483-3p组大鼠胶原纤维减少。
Claims (4)
1.本发明涉及miRNA-483-3p在调控自发性高血压大鼠血压、心脏及血管方面的作用,其特征在于从尾静脉注射miR-483-3p sponge后,自发性高血压大鼠的血压能够保持在初始范围内而不再持续升高,心脏结构和功能得到明显改善,腹主动脉结构、厚度、内膜完整性得到不同程度的改善。
2.如权利要求1所述的血压能够保持在初始范围内,其特征在于自发性高血压大鼠的收缩压、舒张压、平均动脉压都能保持在初始范围内,而不再持续升高。
3.如权利要求1所述的心脏结构和功能得到明显改善,其特征在于射血分数和左室短轴缩短率明显升高,心脏重量指数下降。
4.如权利要求1所述的腹主动脉结构、厚度、内膜完整性得到不同程度的改善,其特征在于大鼠腹主动脉胶原纤维减少,内膜明显变薄,管腔变宽,内皮细胞排列整齐,内膜结构趋于正常。
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