CN102764438A - β3肾上腺素受体激动剂的新用途 - Google Patents

β3肾上腺素受体激动剂的新用途 Download PDF

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CN102764438A
CN102764438A CN2012100208439A CN201210020843A CN102764438A CN 102764438 A CN102764438 A CN 102764438A CN 2012100208439 A CN2012100208439 A CN 2012100208439A CN 201210020843 A CN201210020843 A CN 201210020843A CN 102764438 A CN102764438 A CN 102764438A
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林曙光
郑猛
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Abstract

本发明公开了β3肾上腺素受体激动剂的新用途。经过大量实验证实，β3肾上腺素受体是调控SIRT1、mTOR和p53的重要因子，因此β3肾上腺素受体激动剂可以用于制备治疗SIRT1、mTOR和p53信号通路相关疾病的药物，如恶性肿瘤、肥厚型心肌病、肺动脉高压、肝硬化、类风湿性关节炎、肾功能衰竭和阿尔茨海默病等。本发明β3肾上腺素受体激动剂具有广阔的应用前景。

Description

β3肾上腺素受体激动剂的新用途
技术领域
本发明涉及信号通路领域，具体涉及β3肾上腺素受体激动剂在制备治疗新疾病的药物中的新用途。
背景技术
人体内的β3肾上腺素受体主要表达在脂肪细胞，尤其在内脏脂肪细胞，促进脂肪分解供能。目前已发现了多种选择性作用于该受体的激动剂与阻滞剂。对于β3受体的药物研究主要基于其促脂解作用，将β3受体激动剂作为减肥药。但是，对于β3受体在衰老相关性疾病的发生、发展中的地位和其潜在治疗作用，尚无相关报道。
抑癌基因TP53可能是调控衰老和细胞程序重排的关键基因，TP53是一个衰老相关基因，且其抑癌作用与衰老密切相关。它通过调节 DNA的损伤、自由基生成与清除等控制细胞衰老，p53过度活跃引起干细胞早衰，p53本身的修饰是维持其功能的主要原因。大量研究表明Sirtuin 1 (SIRT1)可通过对p53的去乙酰化作用在p53介导的老化和抗肿瘤反应中发挥关键性的作用。酵母沉默信息调节因子2(Silent Information Regulator 2，SIR2)是依赖于烟酰胺腺嘌呤二核苷酸的组蛋白去乙酰化酶，SIRT1是与哺乳动物Sir2同源性最高的家族成员，SIRT1蛋白存在于哺乳动物细胞质和细胞核中，对细胞生存、衰老和氧化应激等起到十分重要的调节作用。SIRT1使p53去乙酰化，抑制其转录活性。此外SIRT1能通过募集到p53靶启动子处，导致低乙酰化核小体转录沉默。
发明内容
本发明公开了β3肾上腺素受体(adrenergic beta-3-receptor，ADRB3)是调控SIRT1，p53，mTOR(mammalian target of rapamycin, 哺乳动物雷帕霉素靶蛋白), MIF和microRNA-16信号通路的重要受体。本发明公开了β3肾上腺素受体激动剂的用途，用于治疗与mTOR /SIRT1/p53信号通路相关的疾病，如心肌肥大、肥厚型心肌病、心肌纤维化、肺动脉高压、肝硬化、肾功能衰竭、阿尔茨海默病、和恶性肿瘤等。本发明公开了β3肾上腺素受体激动剂在制备抗衰老药物的应用。本发明公开了β3肾上腺素受体激动剂在预防干细胞衰老的应用。本发明还公开了β3肾上腺素受体激动剂作为提高诱导多能干细胞（Induced pluripotent stem cells，iPS）效率的药物的应用。本发明人发现β3受体阻滞剂可以减少肿瘤和其外周脂肪组织中的SIRT1表达，导致p53乙酰化，提高p53的转录活性，增加肿瘤组织中p53，促进肿瘤细胞衰老、凋亡并阻断远处转移。β3受体激动剂则可增加SIRT1表达，减少p53，激活mTOR, 下调miR-16-1和miR-15a表达，起到抗衰老作用。本发明人还发现激动β3受体可以减少mTOR蛋白表达，特别是抑制mTOR-Rictor复合物。本发明人还发现激动β3受体可以减少线粒体自噬，β3受体激动剂可用作自噬拮抗剂。
可用于本发明的β3受体激动剂没有特别的限制，所有能够兴奋β3受体的化合物都适用于本发明。代表性的β3受体激动剂的例子包括(但不限于)：BRL 37344，SR58611A，TAK2677，N25984等。
本发明的β3受体激动剂的剂型和制备方法没有特别限制，可用本领域常规通用的制法制成片剂、胶囊、颗粒剂、缓释剂、注射剂等各种剂型。
本发明的β3受体激动剂可以作为治疗心肌肥大、心肌纤维化、肺动脉高压、肝硬化、阿尔茨海默病和恶性肿瘤的药物。β3受体激动剂也可以作为SIRT1的激动剂而用于抗衰老。
本发明的β3受体激动剂可以提高诱导多能干细胞（Induced pluripotent stem cells，iPS）生产效率，减缓干细胞衰老和老化，延缓脂肪干细胞和心肌干细胞的衰老和老化。
此外应理解，在阅读了本发明的以上描述的内容之后，本领域的技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
附图说明
图1为SR59230A增加MCF-7细胞中p53的表达；
图2为SR59230A减少MCF-7细胞中SIRT1的表达；
图3为BRL37344减少心衰大鼠心肌凋亡；
图4为BRL37344减少心肌p53、增加SIRT1；
图5为BRL37344改善心衰大鼠心功能；
图6为脂肪干细胞中β-半乳糖苷酶染色；
图7为Rictor定量PCR；
图8为mTOR定量PCR;
图9为SIRT1, 3, 4定量PCR。
具体实施方式
以下结合实施例来进一步解释本发明，但实施例并不对本发明做任何形式的限定。
实施例1
阻滞β3受体减少MCF-7细胞中SIRT1，增加p53表达。不同浓度的SR59230A处理MCF-7细胞，24h后裂解细胞，提取总蛋白。BCA法测定蛋白浓度，取10ug蛋白，10% SDSPAGE分离后将蛋白转至PVDF膜上，用含4％脱脂牛奶的TBST(10 mmol/L Tris HC1，pH 7.5，150 mmol/L NaC1，0.1％Tween 20)封闭膜1 h，p53抗体（1∶1000），SIRT1抗体（1∶1000），4℃，孵育过夜，洗膜后用二抗孵育1 h，ECL显色，实验重复3次。Fluorchem 8900软件分析蛋白质条带的灰度值，计算目的条带与内参条带（GAPDH）的比值。结果如图1、2示，随着SR59230A浓度的增加，p53表达增加，而SIRT1逐渐减少。
实施例2
在心肌梗死大鼠模型中，兴奋β3受体可以增加心肌细胞SIRT1，并减少p53表达，改善心功能，发挥抗凋亡作用。结扎大鼠左冠状动脉前降支，造成心梗模型。腹腔注射BRL37344 1mg/kg/day，4周后做心脏b超。取心脏组织检测凋亡（tunel法）和SIRT1、p53表达（western blot）。取心脏，测量左心室重和全心重比值（LVW/BW）。结果如图3～5，BRL37344减少心肌p53，并增加SIRT1，减少心肌细胞凋亡，减少心衰大鼠LVW/BW，逆转心肌肥厚，改善心功能。
实施例3
阻滞β3受体增加脂肪干细胞中β-半乳糖苷酶，促进干细胞老化。采用BRL37344和SR59230A各10-7M的处理大鼠脂肪干细胞，24h后，多聚甲醛固定，按照β-半乳糖苷酶染色试剂盒说明染色、摄片。结果如图6所示：与SR59230A相比，BRL37344减少脂肪干细胞中β-半乳糖苷酶，说明激动脂肪干细胞的β3肾上腺素受体可以起到抗衰老作用。
实施例4
兴奋β3受体可减少心肌细胞mTOR-Rictor复合物。采用BRL37344和SR59230A各10-7M的处理大鼠心肌细胞，8h后，提取总RNA，反转录后，做定量PCR，检测mTOR和Rictor基因表达。结果如图7、8所示：与对照组相比，BRL37344减少mTOR-Rictor复合物。
实施例5
兴奋β3受体增加衰老大鼠心脏、肝脏、大脑、肾脏和主动脉中的SIRT1、SIRT3及SIRT4表达。20只12月龄雄性SD大鼠，随机分为2组，BRL37344 100nmol/只，腹腔注射，qd，连用2周。对照组给予相同体积溶剂。大鼠处死后取心脏、肝脏、大脑、肾脏和主动脉，提取总RNA，反转录后，做定量PCR，检测SIRT1、SIRT3及SIRT4基因表达。结果如图9所示：与对照组相比，BRL37344增加心脏、肝脏、大脑、肾脏和主动脉中SIRT1、SIRT3及SIRT4表达。
实施例6
兴奋β3受体增加大鼠心肌细胞线粒体含量。采用BRL37344 10-7M的处理大鼠乳鼠心肌细胞，MitoTracker线粒体探针检测线粒体数量，JC1测线粒体膜电位，荧光探针DCFH-DA检测胞内活性氧(reactive oxygen species, ROS)含量，ATP试剂盒检测胞内ATP水平，流式仪检测MDC染色，大鼠心肌细胞转染GFP-LC3真核表达载体。结果发现，BRL37344增加胞内线粒体含量，维持细胞线粒体膜电位，减少胞内ROS含量，增加胞内ATP水平。SR59230A增加MDC染色，减少线粒体，损伤线粒体膜电位，促进形成多个明亮的绿色荧光斑点。
总结：
本发明揭示了β3肾上腺素受体的信号通路，即β3受体调控mTOR，SIRT1，p53等蛋白的表达和活性，对于肿瘤、代谢性疾病、免疫系统疾病以及衰老相关性疾病的发生、发展有重要意义。β3受体可作为治疗靶点，通过调控β3受体，治疗以上疾病。

Claims (10)

1.β3肾上腺素受体激动剂在制备SIRT1、SIRT3和SIRT4激动剂中的应用。
2.β3肾上腺素受体激动剂在制备mTOR抑制剂中的应用。
3.β3肾上腺素受体激动剂在制备p53抑制剂中的应用。
4.β3肾上腺素受体激动剂在制备治疗SIRT1、mTOR和p53信号通路相关疾病的药物中的应用。
5.β3肾上腺素受体激动剂在制备治疗心肌肥大、心肌纤维化、肺动脉高压、肝硬化、肾功能衰竭、阿尔茨海默病和恶性肿瘤的药物中的应用。
6.β3肾上腺素受体激动剂在制备抗动脉粥样硬化、抗冠状动脉支架内再狭窄或冠状动脉药物支架涂层药物中的应用。
7.β3肾上腺素受体激动剂在制备心脏停搏保护液中的应用。
8.β3肾上腺素受体激动剂在制备抗衰老药物中的应用。
9.β3肾上腺素受体激动剂在制备提高诱导多能干细胞效率的药物中的应用。
10.β3肾上腺素受体激动剂在制备抗干细胞衰老药物中的应用。
CN2012100208439A 2012-01-30 2012-01-30 β3肾上腺素受体激动剂的新用途 Pending CN102764438A (zh)

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CN108913655A (zh) * 2018-07-16 2018-11-30 浙江大学 基于多能干细胞技术建立“人源性”心肌肥大模型的方法

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ES2394349B1 (es) 2012-08-29 2013-11-04 Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii Uso de agonistas selectivos de receptores beta-3 adrenérgicos para el tratamiento de hipertensión pulmonar
WO2017106584A1 (en) * 2015-12-16 2017-06-22 The Board Of Trustees Of The Leland Stanford Junior University Treatment of central nervous system and mental disorders with agonists of beta-3 adrenoceptor

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