CN103467596A - 一个治疗肺动脉高压的新靶点 - Google Patents

一个治疗肺动脉高压的新靶点 Download PDF

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CN103467596A
CN103467596A CN2012101831319A CN201210183131A CN103467596A CN 103467596 A CN103467596 A CN 103467596A CN 2012101831319 A CN2012101831319 A CN 2012101831319A CN 201210183131 A CN201210183131 A CN 201210183131A CN 103467596 A CN103467596 A CN 103467596A
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ht2br
treatment
pulmonary
pah
target spot
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汪南平
刘雅涵
赵蓓蕾
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Peking University
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Peking University
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Abstract

本发明公开了一个治疗肺动脉高压的新靶点。该治疗肺动脉高压新靶点针对五羟色胺2B型受体(5-HT2BR)，肺动脉高压的显著性特点为肺动脉的高收缩性，抑制5-HT2BR活性可明显抑制肺动脉的收缩功能，该受体可以作为新的肺动脉高压的治疗靶点。

Description

一个治疗肺动脉高压的新靶点
技术领域
本发明涉及五羟色胺2B型受体(5-HT2BR)通过参与肺动脉的收缩从而在肺动脉高压过程中起到重要作用，从而作为治疗肺动脉高压的新靶点。
背景技术
肺动脉高压(pulmonary arterial hypertension，PAH)是以肺动脉高收缩性和血管重构为特点并伴随肺动脉压力增高，右心室衰竭的慢性疾病[1]，PAH已成为一类严重威胁人类身心健康的常见疾病。正常人在静息状态下肺动脉压力为12-16mmHg，而当肺动脉压力高于25mmHg时，即被定义为肺动脉高压。PAH的主要症状包括呼吸短促，头晕和晕厥，胸疼等。PAH分为原发性与继发性。继发性肺动脉高压常与药物、毒素、HIV感染、胶原血管病-硬皮病、慢性阻塞性肺病(COPD)、间质性肺病(ILD)、睡眠呼吸障碍、肺泡通气不足等有关。PAH没有有效的治疗药物，现有治疗方法仅能缓解PAH发病过程。利尿药和强心药通过调节心脏功能缓解PAH症状，但不针对PAH发病原因；钙离子通道阻断剂和内皮素受体阻断剂属于血管舒张类药物，仅适用于少数人群；吸氧是常规治疗方法。因此目前对PAH潜在的有效治疗靶点的研究有广阔的应用前景。
PAH与内皮素-1(ET-1)、血栓素A2(TXA2)、一氧化氮(NO)、前列环素(PGI2)、转化生长因子(TGFβ)等血管舒缩及细胞增殖相关因子有密切关系。五羟色胺(5-hydroxytryptamin，5-HT)在PAH中有重要的病理生理意义，这种观点于20世纪中旬被提出。这是由于减肥药aminorex的使用在20世纪60年代在奥地利、德国及瑞士等国家引起PAH的广泛流行，而fenfluramine与dexfenfluramine于20世纪末在欧美国家广泛使用导致了又一批PAH的高发。Aminorex和fenfluramine药物具有抑制5-HT的吸收作用且促进5-HT的释放，造成患者血浆中5-HT浓度明显增高，从而诱导了PAH的发生[2-4]。研究发现，连续服用dexfenfluramine三个月，罹患PAH的几率增加了23倍[4]。上述事实提示5-HT在PAH发病过程中具有重要作用。
5-HT具有多种受体，其中受体5-HT1B、2A和2B存在于肺动脉中[5]。PAH肺动脉5-HT2BR的表达水平升高，而敲除5-HT2BR或使用其抑制剂可以逆转缺氧诱导的小鼠PAH的发生发展过程[6]。提示5-HT2BR在PAH发病过程中具有关键作用。但5-HT2BR在PAH中的作用机制及其调控还不清楚。
发明内容
本发明的目的是提供一种在肺动脉高压过程中参与血管收缩的受体5-HT2BR，作为肺动脉高压治疗的新靶点。
本发明所提供5-HT2BR蛋白序列号为：NP_058946.1
附图说明
图1为5-HT2BR在肺动脉高压大鼠中表达增高
A，B为在肺动脉中利用免疫组化染色检测5-HT2BR表达结果
C，D为在肺动脉中利用western blot检测5-HT2BR表达结果
E，F为在肺动脉中利用PCR检测5-HT2BR表达结果
图2为5-HT2BR特异性激动剂诱导的肺动脉收缩在肺动脉高压大鼠中增强
A，B为在野百合碱(monocrotaline，MCT)诱导的肺动脉高压大鼠中5-HT2BR介导的肺动脉收缩
C，D为在慢性缺氧诱导的肺动脉高压大鼠中5-HT2BR介导的肺动脉收缩
具体实施方式
图1为5-HT2BR在肺动脉高压大鼠中表达增高
实验建立了两种肺动脉高压大鼠模型，野百合碱(monocrotaline，MCT)及慢性缺氧(chronichypoxia，CH)诱导的PAH大鼠模型。单次皮下注射60mg/Kg剂量的MCT，3周后即可形成PAH大鼠模型。慢性缺氧PAH大鼠模型的建立是将大鼠置于10％氧气浓度的环境下持3周，即可形成肺动脉高压大鼠模型。
我们利用免疫组化实验方法观察肺动脉5-HT2BR在PAH疾病过程中的表达。使用肺动脉冰冻切片进行5-HT2BR免疫组化染色，发现在MCT及CH大鼠肺动脉平滑肌中，5-HT2BR表达增高。提取肺动脉蛋白及mRNA，利用Western blot和RT-qPCR检测5-HT2BR表达水平，也证实了这一变化。
图2为5-HT2BR特异性激动剂诱导的肺动脉收缩在肺动脉高压大鼠中增强
在5-HT2BR表达变化的基础上，我们利用离体微血管张力测定仪检测5-HT2BR介导的肺动脉收缩功能的变化。分离大鼠的肺动脉，置于微血管离体张力测定仪中，在37℃预热的krebs液平衡90分钟，L-NAME预处理10分钟以排除内皮舒张功能。使用5-HT2BR特异性激动剂BW723C86刺激血管，观察血管张力变化。结果显示正常大鼠肺动脉对于5-HT2BR激动剂基本无收缩反应，但在MCT或慢性缺氧诱导的PAH大鼠中，BW723C86诱导的肺动脉收缩明显增强，这一实验说明PAH肺动脉的高收缩性是由5-HT2BR介导的。

Claims (1)

1.一个治疗肺动脉高压的新靶点。该治疗肺动脉高压新靶点针对五羟色胺2B型受体(5-HT2BR)，肺动脉高压的显著性特点为肺动脉的高收缩性，抑制5-HT2BR活性可明显抑制肺动脉的收缩功能，该受体可以作为新的肺动脉高压的治疗靶点。
CN2012101831319A 2012-06-06 2012-06-06 一个治疗肺动脉高压的新靶点 Pending CN103467596A (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105561313A (zh) * 2016-01-25 2016-05-11 北京大学 降低5-ht2br含量和抑制其活性的物质在制备治疗和预防动脉粥样硬化产品中的应用
RU2627463C1 (ru) * 2016-07-19 2017-08-08 Федеральное государственное бюджетное научное учреждение "Иркутский научный центр хирургии и травматологии" Способ моделирования гипертензии малого круга кровообращения

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048412A (zh) * 2004-09-23 2007-10-03 Epix特拉华公司 哌啶基氨基－噻吩并[2,3－d]嘧啶化合物
WO2008061966A2 (en) * 2006-11-22 2008-05-29 Boehringer Ingelheim International Gmbh New use of flibanserin
WO2008061968A1 (en) * 2006-11-22 2008-05-29 Boehringer Ingelheim International Gmbh Benzimidazolone derivates in the treatment of pulmonary arterial hypertension
WO2012028614A1 (en) * 2010-09-01 2012-03-08 Janssen Pharmaceutica Nv 5-ht2b receptor antagonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048412A (zh) * 2004-09-23 2007-10-03 Epix特拉华公司 哌啶基氨基－噻吩并[2,3－d]嘧啶化合物
WO2008061966A2 (en) * 2006-11-22 2008-05-29 Boehringer Ingelheim International Gmbh New use of flibanserin
WO2008061968A1 (en) * 2006-11-22 2008-05-29 Boehringer Ingelheim International Gmbh Benzimidazolone derivates in the treatment of pulmonary arterial hypertension
WO2012028614A1 (en) * 2010-09-01 2012-03-08 Janssen Pharmaceutica Nv 5-ht2b receptor antagonists

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105561313A (zh) * 2016-01-25 2016-05-11 北京大学 降低5-ht2br含量和抑制其活性的物质在制备治疗和预防动脉粥样硬化产品中的应用
CN105561313B (zh) * 2016-01-25 2018-12-25 北京大学 降低5-ht2br含量和抑制其活性的物质在制备治疗和预防动脉粥样硬化产品中的应用
RU2627463C1 (ru) * 2016-07-19 2017-08-08 Федеральное государственное бюджетное научное учреждение "Иркутский научный центр хирургии и травматологии" Способ моделирования гипертензии малого круга кровообращения

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