CN107303390A - Dpp4抑制剂在制备治疗低氧性肺动脉高压药物中的用途 - Google Patents
Dpp4抑制剂在制备治疗低氧性肺动脉高压药物中的用途 Download PDFInfo
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- CN107303390A CN107303390A CN201710045986.8A CN201710045986A CN107303390A CN 107303390 A CN107303390 A CN 107303390A CN 201710045986 A CN201710045986 A CN 201710045986A CN 107303390 A CN107303390 A CN 107303390A
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- dpp4
- pulmonary hypertension
- sitagliptin
- hypoxic
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Abstract
本发明属生物技术领域，涉及DPP抑制剂的新的药用用途，具体涉及DPP4抑制剂sitagliptin在制备治疗低氧性肺动脉高压药物中的用途。本发明通过在细胞水平采用Western blot技术和建立细胞损伤修复模型，结果表明，DPP4在低氧诱导的PASMCs中高表达，低氧可促进PASMCs迁移，DPP4抑制剂sitagliptin可抑制低氧诱导的PASMCs的迁移；通过建立大鼠低氧性肺动脉高压模型，结果表明，与常氧组相比DPP4在低氧性肺动脉高压大鼠肺组织中高表达，低氧模型组大鼠右心室压力、右心室肥厚指标明显增高，肺小血管肥厚增加，DPP4抑制剂sitagliptin抑制低氧性肺动脉高压大鼠右心室压力、右心室肥厚形成，减轻肺小血管肥厚的程度。本发明为预防和治疗低氧性肺动脉高压疾病提高了新的干预手段。
Description
技术领域
本发明属生物医学技术领域，涉及DPP抑制剂的新的药用用途，具体涉及DPP4抑制剂sitagliptin在制备治疗低氧性肺动脉高压药物中的用途。
背景技术
临床实践显示，低氧性肺动脉高压（Hypoxic pulmonary hypertension，HPH）是一种难治性的疾病，其特征性表现为肺血管平滑肌细胞的增殖和渐进性的肺血管重构。至今为止，本领域尚未完全清楚该低氧性肺动脉高压的发病机制，业内普遍认为，肺血管收缩和血管重构为其主要的病理机制。尽管目前已有多种药物应用于肺动脉高压（Pulmonaryarterial hypertension，PAH）的治疗，但均未能有效的抑制和逆转肺血管重构的发生。研究显示，肺血管重构的病理过程主要包括以下三个环节：肺血管内皮细胞向间充质细胞（血管平滑肌细胞）的转化；血管间充质细胞向内皮下方的迁移；内皮细胞、平滑肌细胞以及成纤维细胞的增殖和抗凋亡过程。故而，研究肺血管重构的发生机制及药物治疗在PAH的临床治疗中有重要意义。
DPP4，又被称为T细胞表面抗原CD26，是一种细胞表面的丝氨酸蛋白酶，DPP-4在肠中高表达，此外于肝脏、胰腺、胎盘、胸腺等也有表达，部分以可溶形式存在于循环血液中；研究显示，细胞表面和可溶性的DPP-4均具有酶活性，其主要作用是优先将氨基末端第2个氨基酸为丙氨酸（Ala）或脯氨酸（Pro）的寡肽的氨基末端前两个氨基酸剪切去除；研究表明，DPP4主要的作用是分解体内的蛋白质，。其中一种被DPP4分解的蛋白质叫做GLP─1，它是由肠道细胞分泌的荷尔蒙，GLP-1可以通过可以刺激胰岛素、抑制升糖素、抑制胃排空和让胰岛细胞重生的方式来降低血糖，导致DPP4失活从而不分解GLP-1的DPP4抑制剂已经成为治疗糖尿病的主攻方向之一。
Sitagliptin是目前研究最为深入并已经应用于临床的DPP4抑制剂，它是一种竞争性DPP4抑制剂，通过与DPP4高保守的β-螺旋区谷氨酸盐残基Glu205和Glu206非共价结合，抑制其酶活性。2006年10月美国食品级药物管理局（FDA）批准sitagliptin用于2型糖尿病的治疗。有文献报道sitagliptin在体外通过一种包括cAMP/PKA/Rac1激活在内的通路减少孤立脾脏CD4 T细胞迁移 。
基于现有技术的研究现状，本申请的发明人拟提供DPP抑制剂新的药用用途，尤其是DPP4抑制剂sitagliptin在制备治疗低氧性肺动脉高压药物中的用途。
发明内容
本发明的目的是提供DPP抑制剂新的药用用途，尤其是DPP4抑制剂sitagliptin在制备治疗低氧性肺动脉高压药物中的用途。
本发明经研究证实，在肺动脉平滑肌细胞中，sitagliptin能抑制细胞迁移从而抑制肺血管重构发生进而可用于治疗低氧性肺动脉高压，提供了sitagliptin药物在制备治疗低氧性肺动脉高压药物中新用途，解决了现有的药物中不能抑制肺血管重构的问题。
本发明的第一方面是提供一种包含DPP4（二肽基肽酶-4，dipeptidyl peptidase4）抑制剂的药物组合物，所述药物组合物含有任一项所述的DPP4抑制剂化合物或其药学上可接受的盐、前药、溶剂化物，以及药学上可接受的载体或赋形剂。
本发明的第二方面，提供的DPP4抑制剂包含但不限于以下几种，即西他列汀（Sitagliptin）、维格列汀（vildagliptin）、沙格列汀（saxagliptin）、阿拉格列汀（anagliptin）、阿格列汀（alogliptin）、吉格列汀（gemigliptin）、特里列汀（Teneligliptin）、利格列汀（Linagliptin）、瑞格列汀（retagliptin）、奥格列汀（omarigliptin）、哥格列汀（gosogliptin）、denagliptin、carmegliptin、evogliptin、曲格列汀（trelagliptin）、melogliptin、Dutagliptin等。
本发明的第三方面，提供一种药物组合物，其特征在于，所述药物组合物含有上述的化合物或其药学上可接受的盐或前药，以及药学上可接受的载体或赋形剂。
本发明的第四方面，提供的药物组合物可制成适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。
本发明的第五方面，提供的所述的化合物的药物组合物及其在制备治疗或预防大鼠及人低氧性肺动脉高压药物中的治疗应用，所述应用中，包括将上述的化合物或所述的药物组合物给予有此需要的对象。
本发明的目的通过下述技术方案施现：
1.细胞水平：采用培养的原代大鼠肺动脉平滑肌细胞（Pulmonary arterial smoothcells，PASMCs）；
①将细胞分为常氧对照组和低氧组（1%氧浓度），分别培养24h后，提取蛋白，用Westernblot技术检测DPP4蛋白水平的表达情况；
②将细胞分为三大组：常氧对照组；低氧组；低氧+sitagliptin组（分三个浓度：100μM，200μM，500μM）；
建立细胞损伤修复模型，常氧组放置于常规细胞培养箱培养，低氧组放置于1%低氧细胞培养箱培养，低氧+sitagliptin组给予不同浓度sitagliptin后放置于1%低氧培养箱培养，分别于0h、48h拍照，观察各组细胞迁移的情况；
2.动物水平：采用SD大鼠建立低氧性肺动脉高压模型，观察sitagliptin对大鼠低氧性肺动脉高压的治疗作用；
将SD大鼠随机分为三大组（每组8只）：正常对照组；低氧对照组；低氧+sitagliptin组（设三个浓度：1mg/kg,2mg/kg,5mg/kg），常氧对照组置于常压常氧环境下饲养，低氧组大鼠放置于全自动调节低压低氧舱（大气压为55 kPa，氧浓度为10 %）内，给予间断性低压低氧处理，每天8 h，连续4周，低氧+sitagliptin组大鼠每日低压低氧处理前给予sitagliptin相应剂量灌胃，所有动物均给予人性化管理，自由饮水及摄食；
①4周后用Western blot检测常氧组和低氧组大鼠肺组织中DPP4蛋白的表达情况；
②4周后测定各组大鼠右心室压力、右心肥厚指标，观察各组肺组织中肺小血管肥厚的情况。
实验结果表明，DPP4在低氧诱导的PASMCs和大鼠低氧性肺动脉高压模型肺组织中均是高表达的，DPP4的抑制剂sitagliptin可以抑制低氧诱导的PASMCs的迁移，并且降低低氧性肺动脉高压大鼠的右心室压力、右心肥厚指标，减轻肺小血管的肥厚；所述DPP4抑制剂可用于制备治疗低氧性肺动脉高压的药物。
本发明的有益效果是：
本发明提供了DPP4抑制剂在低氧性肺动脉高压中的治疗作用，DPP4抑制剂可以抑制低氧诱导的PASMCs的迁移；降低了低氧性肺动脉高压大鼠的右心室压力、右心肥厚指标，减轻肺小血管的肥厚。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案，例如，新的或优选的技术方案包括：供一种包含DPP4（二肽基肽酶-4，dipeptidyl peptidase 4）抑制剂的药物组合物，所述药物组合物含有任一项所述的DPP4抑制剂化合物或其药学上可接受的盐、前药、溶剂化物，以及药学上可接受的载体或赋形剂；所述的DPP4抑制剂包含但不限于以下几种，即西他列汀（Sitagliptin）、维格列汀（vildagliptin）、沙格列汀（saxagliptin）、阿拉格列汀（anagliptin）、阿格列汀（alogliptin）、吉格列汀（gemigliptin）、特里列汀（Teneligliptin）、利格列汀（Linagliptin）、瑞格列汀（retagliptin）、奥格列汀（omarigliptin）、哥格列汀（gosogliptin）、denagliptin、carmegliptin、evogliptin、曲格列汀（trelagliptin）、melogliptin、Dutagliptin等；一种药物组合物，其含有上述的化合物或其药学上可接受的盐或前药，以及药学上可接受的载体或赋形剂；药物组合物可制成适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂；所述的化合物的药物组合物及其在治疗或预防大鼠及人低氧性肺动脉高压的治疗应用方法等。
附图说明
图1.DPP4抑制剂抑制低氧性肺动脉高压大鼠右心室压力、右心室肥厚的形成，减轻肺小血管肥厚的程度，
其中，A：低氧组大鼠压力与常氧组相比明显增高，应用DPP4抑制剂后可降低低氧性肺动脉高压大鼠右心室压力(1 mmHg = 0.133 kPa)；B.C：低氧组大鼠右心室肥厚指标（RV/BW、RV/LV+S）与常氧组相比明显增高，应用DPP4抑制剂后可降低低氧性肺动脉高压大鼠右心室肥厚指标；D：采用HE染色法观察各组大鼠肺组织中肺小血管管壁肥厚程度，结果提示低氧组大鼠肺小血管肥厚程度与常氧组相比明显增厚，应用DPP4抑制剂后可降低低氧性肺动脉高压大鼠肺小血管肥厚程度；
1. Saxagliptin，2. Sitagliptin， 3. Alogliptin.
***P<0.001 vs. normoxia group；# P<0.05，## P<0.01，### P<0.001 vs. hypoxiagroup。
图2.建立PASMCs损伤修复模型，采用划痕实验检测各组PASMCs细胞迁移情况，发现与常氧组相比低氧处理促进细胞迁移，应用sitagliptin后可抑制PASMCs迁移。
具体实施方式
下面结合附图和具体实施方式对本发明进行详细说明。
1）实验动物：健康雄性SD(Sprague Dawley)大鼠，体重150-200 g，由第四军医大学实验动物中心提供；
2）动物模型的建立及分组：根据实验需要，将40只SD大鼠随机分为常氧对照组、低氧组、低氧+治疗组（1mg/kg）（设三种药物：Saxagliptin、Sitagliptin和Alogliptin；低氧处理前灌胃相应剂量药物），每组8只，大鼠肺动脉高压模型的建立采用低压低氧法：将大鼠放置于全自动调节低压低氧舱（大气压为55 kPa，氧浓度为10 %）内，给予间断性低压低氧处理，每天8 h，连续4周，常氧对照组置于常压常氧环境下饲养，所有动物均给予人性化管理，自由饮水及摄食：
3）血流动力学检测：大鼠称量体重（Body weight，BW）后，用0.2 g/mL的乌拉坦麻醉大鼠，经右颈静脉插管至右心室，用压力监测仪记录右心室压力（Right ventriclepressure，RVP），测压完成后处死大鼠，游离心脏和肺组织；取出心脏，剪去心房及大血管、脂肪等组织，分离出右心室（Right ventricle，RV）和左心室+室间隔（Left ventricleplus septum，LV+S），用滤纸充分吸干表面水分后分别称重，计算RV/BW、RV/(LV+S)比值；
4）肺动脉重构的病理学检测：大鼠血流动力学指标测定后，剪断大鼠左侧颈总动脉，自右侧颈静脉灌注生理盐水冲洗剩余的血液，取大鼠左侧肺叶，用4 %多聚甲醛缓冲液固定24h，常规石蜡包埋、切片，行HE染色，染色后，光镜下观察各组大鼠肺血管形态学改变；
5）SD大鼠原代肺动脉平滑肌细胞（Pulmonary arterial smooth cells，PASMCs）的培养及分组：SD大鼠用0.2 g/mL乌拉坦腹腔注射麻醉后，在超净工作台上，取下肺动脉主干，去除纤维外膜，PBS冲洗至无血迹，将其剪至1 mm3大小的组织块，移入培养瓶底面，加入含胎牛血清的DMEM高糖培养液，将培养瓶倒置放入37 ℃，5 % CO2温箱中2 h，2 h后翻瓶，继续培养，每3 d换液一次，待细胞生长融合后传代，采用生长状态良好的3～5代细胞进行后续实验；
6）细胞迁移实验：实验分常氧组、低氧组、低氧+Sitagliptin组(分四个浓度：10μM，100μM，200μM，500μM)，将PASMCs按107个细胞/孔，接种于6孔板内，使第二日细胞生长90 %以上融合。细胞贴壁后，换用无血清培养液培养24 h，使细胞生长同步，然后用200 uL枪头比着直尺垂直划直线，PBS洗3次后，Sitagliptin组换用含相应浓度Sitagliptin培养液，其它组给予常规培养液；然后将常氧组放于常规细胞培养箱（21 % O2、5 % CO2）中孵育，低氧组放入低氧培养箱，向其中充入1 % O2、94 % N2和5 % CO2，开始计算缺氧时间，分别于0 h、48 h拍照划痕处；
7）数据采用均数±标准差( ±s)表示。各组比较采用方差分析和q检验，检验水准α=0.05，P<0.05为差异有统计学意义。
实验结果显示，DPP4在低氧诱导的PASMCs和大鼠低氧性肺动脉高压模型肺组织中均是高表达的，DPP4的抑制剂sitagliptin可以抑制低氧诱导的PASMCs的迁移，并且降低低氧性肺动脉高压大鼠的右心室压力、右心肥厚指标，减轻肺小血管的肥厚。
Claims (6)
1.DPP4抑制剂在制备治疗低氧性肺动脉高压药物中的用途。
2.按权利要求1所述的用途，其特征在于，所述的DPP4抑制剂抑制低氧诱导的PASMCs的迁移，降低低氧性肺动脉高压的右心室压力、右心肥厚指标，减轻肺小血管的肥厚。
3.按权利要求1所述的用途，其特征在于，所述的DPP4抑制剂选自西他列汀（Sitagliptin）、维格列汀（vildagliptin）、沙格列汀（saxagliptin）、阿拉格列汀（anagliptin）、阿格列汀（alogliptin）、吉格列汀（gemigliptin）、特里列汀（Teneligliptin）、利格列汀（Linagliptin）、瑞格列汀（retagliptin）、奥格列汀（omarigliptin）、哥格列汀（gosogliptin）、denagliptin、carmegliptin、evogliptin、曲格列汀（trelagliptin）、melogliptin或Dutagliptin。
4.按权利要求1所述的用途，其特征在于，所述的低氧性肺动脉高压是大鼠或人低氧性肺动脉高压。
5.一种包含DPP4（二肽基肽酶-4，dipeptidyl peptidase 4）抑制剂的药物组合物，其特征在于，所述药物组合物含有权利要求3所述的任一所述的DPP4抑制剂化合物或其药学上可接受的盐、前药、溶剂化物，以及药学上可接受的载体或赋形剂。
6.按权利要求5所述的药物组合物，其特征在于，所述药物组合物是适于口服的剂型，选自片剂、溶液剂、混悬液、胶囊剂、颗粒剂或粉剂。
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