CN108743917A - 外源性Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的应用 - Google Patents
外源性Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的应用 Download PDFInfo
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Abstract
本发明属于药物新用途技术领域，具体公开了外源性Cyclo(‑RGDfK)多肽在制备防治肺动脉高压病药物中的应用，申请人发现外源性Cyclo(‑RGDfK)多肽能够调控肺动脉高压模型大鼠肺组织中Rac1和RhoA的活性，从而抑制野肺动脉高压模型大鼠肺动脉平滑肌细胞增殖。治疗性研究结果显示，外源性RGD多肽具有显著抑制肺动脉平滑肌细胞增殖、降低右室收缩压力、降低右室重量与左室加室间隔重量比值的疗效。本发明首次公开了外源性Cyclo(‑RGDfK)多肽在治疗肺动脉高压病中的作用，为治疗肺动脉高压病提供了药物基础。
Description
技术领域
本发明属于药物新用途技术领域，具体地说，涉及外源性Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的应用。
背景技术
肺动脉高压(pulmonary hypertension，PH)是以肺动脉压和肺血管阻力升高为特征的临床血流动力学症候群。其发生发展的重要病理生理基础为肺血管收缩、内皮细胞与平滑肌细胞的增殖和原位血栓形成。这意味着存在血管扩张剂和血管收缩剂，生长抑制剂和促有丝分裂因子以及抗血栓形成和促血栓形成决定因子之间的正常关系中的扰动。这些稳态失衡可能是肺血管内皮细胞功能障碍或损伤的后果。PH可导致右心衰竭，甚至直接导致死亡。PH的发病机制非常复杂，涉及前列环素途径、NO途径、内皮素途径以及外界环境因素(缺氧、中枢神经系统的兴奋)，还有一些与PH相关的疾病，比如硬皮病、人类免疫缺陷病毒(HIV)感染，人类疱疹病毒(HHV)，门静脉高压症，血小板增多症，血红蛋白病和遗传性出血性毛细血管扩张症。近年来关于PH的机制研究有一定进展，但PH的发病机制仍尚不明确。可选择的治疗肺动脉高压的药物有限。
Cyclo(-RGDfK)多肽是含有精氨酸-甘氨酸-门冬氨酸(RGD，Arg-Gly-Asp)序列的一类短肽，广泛存在于多种生物体内，是多种生物细胞外基质和血浆蛋白结构中的基本成分，如纤维蛋白、纤链蛋白、层黏连蛋白等均含有此序列。同时，RGD多肽也普遍包含于细胞间识别系统的基本单位，其作为整合素与其配体相互作用的识别位点，能和11种整合素受体特异性的结合，进而促进细胞与细胞之间以及细胞与细胞外基质间的黏附、迁移、浸润和增殖等一系列生理行为。目前已有研究表明整合素在肿瘤新生血管和肿瘤表面高表达，尤其是αvβ3。在肿瘤的侵袭和转移过程中，肿瘤细胞与细胞外基质的黏附是引起侵袭和转移的关键环节，整合素作为细胞黏附分子家族的重要成员，在这一过程中的作用至关重要，而整合素与配体间相互作用的识别位点为RGD，也就是说RGD序列对肿瘤细胞和细胞外基质及肿瘤细胞之间的黏附起着关键作用。根据RGD与整合素受体受体特异性结合的特性，外源性RGD就可以竞争性拮抗整合素与其配体的结合，从而一直整合素的信号通路，组织细胞与细胞外基质的黏附与迁移等，之后系列研究关注于RDG在肿瘤靶向治疗中的应用。目前外源性RGD多肽在肿瘤的显像、诊断及靶向治疗中有一定的应用，如膀胱癌、胶质母细胞瘤、骨肉瘤及成神经细胞瘤等多种实体肿瘤，同时对抑制血管新生也有一定作用。
小G蛋白有Rac1和RhoA均属于小G蛋白，与整合素一样，三者均是与极性相关的分子，且三者均在恶性肿瘤的侵袭和转移过程中发挥重要作用。细胞迁移过程中细胞形态会发生改变，并牵涉到细胞骨架的变化。之前的研究显示细胞骨架可以受到小G蛋白-尤其是Rac1和RhoA的调节。其中，RhoA介导肌动蛋白、肌球蛋白引起的收缩并与应激纤维形成有关，Rac1通过调节薄板的形成使细胞伸展。溶血磷脂酸(lysophosphatidic，LPA)作用胃腺癌细胞后，细胞迁移增加，且RhoA活性明显升高，加用RhoA的抑制剂可以显著抑制LPA对细胞迁移的促进作用，而且可以影响LPA引起的粘着斑形成和细胞骨架重组，此外，也有研究提出RhoA通路在宫颈癌细胞和结肠癌细胞的迁移中发挥着重要作用。在前列腺癌细胞中，LPA可以诱导Rac1相关的细胞骨架-薄板的形成，从而促进迁移。而Rac1的失活可影响细胞骨架的形成，影响LPA引起的细胞迁移，此现象在乳腺癌细胞、脑胶质瘤细胞等细胞中也得到相同的结论，这些研究结果表明Rac1对LPA诱导的细胞迁移以及相关细胞骨架的形成有重要作用。小G蛋白的磷酸化是调节其活性的机制之一，磷酸化后小G蛋白与鸟苷酸解离抑制因子(guanine-nucleotid-dissociation inhibitor,GDI)的亲和力增加，并从包膜转位至胞浆，从而导致小G蛋白失活。而RhoA188丝氨酸位点、Rac171丝氨酸位点的磷酸化均与很多生物学功能相关。已有研究表明西地那非可以通过抑制RhoA磷酸化从而抑制肺动脉高压。同时，血小板源性生长因子可以促进成纤维细胞和血管平滑肌细胞的迁移，结构失活型Rac1可以抑制该生长因子的作用。而生长抑制剂和促有丝分裂因子之间的稳态失衡是参与肺动脉高压病理生理改变的机制之一。
目前治疗肺动脉高压药物包括肺血管扩张剂，抗凝剂及并发症的相关处理。对预后的评估内容包括临床评估(WHO肺动脉高压功能分级和心电图)、运动耐量(6min步行试验距离或心肺运动试验)、B型脑钠肽(BNP)或N末端B型脑钠肽(NT-BNP)、超声心动图和右心导管检查。
目前尚无外源性Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的报道。
发明内容
针对现有技术中存在的不足，本发明的目的在于提供一种外源性Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的新用途。
为了实现上述目的，本发明采取了如下技术方案：
外源性Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的应用，所述的应用包括但不限于用于制备治疗和/或预防肺动脉高压的药物；
外源性Cyclo(-RGDfK)多肽在制备下述产品中的应用，包括：1)作为唯一有效成分，或主效成分之一用于制备成治疗和/或预防肺动脉高压的药物；2)制备成调控肺动脉高压模型大鼠肺组织中Rac1和RhoA活性的产品；3)制备成抑制肺动脉高压大鼠肺动脉平滑肌细胞增殖的产品。
本发明中，所述外源性Cyclo(-RGDfK)多肽与其他抗肺动脉高压的药物联合作为活性成分在制备治疗或预防肺动脉高压的药物中的应用，也属于本发明的保护范围。
以上所述的应用中，优选的，所述药物的剂型为口服制剂或注射剂。
本发明与现有技术相比，具有以下优点：
在本发明中外源性Cyclo(-RGDfK)多肽能够通过调控野百合碱诱导肺动脉高压模型大鼠肺组织中Rac1和RhoA活性，抑制肺动脉高压大鼠肺动脉平滑肌细胞增殖。治疗性研究结果显示，外源性Cyclo(-RGDfK)多肽具有显著抑制肺动脉平滑肌细胞增殖、降低右室收缩压力、降低右室重量与左室加室间隔重量比值的疗效，因此可用于制备成治疗和/或预防肺动脉高压的药物。
附图说明
图1为本发明实施例1中动物实验流程图。
图2为本发明实施例1肺动脉组织HE染色图。
图3为本发明实施例1右室收缩压力、右室重量与左室加室间隔重量比值结果图。
图4为本发明实施例1Western bloting检测对照组、模型组、外源性Cyclo(-RGDfK)多肽治疗组小鼠肺组织Rac1和RhoA活性情况示意图。
图5为Cyclo(-RGDfK)的分子式。
具体实施方式
下面将结合具体的实施例对本发明的技术方案做进一步的详细说明。应理解，所举实施例的目的在于进一步阐述本发明的内容，而不能在任何意义上解释为对本发明保护范围的限制。本发明实施例所用实验方法，如未特别说明，均为本领域的常规方案；所述试剂或材料，如未特别说明，均来源于商业渠道；本发明实施例是以野百合碱诱发的肺动脉高压大鼠为模型对外源性Cyclo(-RGDfK)多肽的治疗作用进行验证，其他诱因导致的肺动脉高压病外源性Cyclo(-RGDfK)多肽对其也有防治作用。
实施例1：
外源性Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的应用：
1)将雄性SD大鼠(4周龄)随机分为3组：对照组、肺动脉高压组和外源性RGD多肽治疗组。各处理组具体操作如下(图1)：
对照组：腹腔注射与野百合碱注射体积等量的生理盐水。
肺动脉高压组：4周龄大鼠单次腹腔注射野百合碱(MCT，40mg/kg)，此后隔日腹腔注射与野百合碱体积等量生理盐水；
治疗组：4周龄大鼠单次腹腔注射野百合碱(MCT，40mg/kg)，同时注射外源性Cyclo(-RGDfK)多肽(图5)(RGD，5mg/kg)，此后隔日注射外源性Cyclo(-RGDfK)多肽(RGD，5mg/kg)
在注射MCT 4周后运用右心导管法检测大鼠形成肺动脉高压后右室收缩压(rightventricularsystolicpressure,RVSP)。然后收获大鼠血浆及按照需要采取不同方法保存各个器官样本并记录体重及器官重量。并进行肺组织病理切片HE染色。WesternBlot检测大鼠肺组织标本中Rac1和RhoA指标。
结果显示，HE染色表明外源性Cyclo(-RGDfK)多肽可以改善野百合碱导致的肺动脉高压大鼠肺动脉平滑肌细胞增殖(图2中A)，肺动脉高压组肺动脉管壁明显增厚，外源性Cyclo(-RGDfK)多肽治疗组较肺动脉高压组管壁厚度明显减小(图2中B)。同时，外源性Cyclo(-RGDfK)多肽可以降低肺动脉高压大鼠的右室收缩压、降低右室重量与左室加室间隔重量比值及右室重量与体重比值(图3中A、B、C、D)。Western Blot检测表明外源性Cyclo(-RGDfK)多肽可调控野百合碱导致的肺动脉高压大鼠肺组织中Rac1和RhoA活性(图4AB)。表明外源性Cyclo(-RGDfK)多肽明显改善了致病模型大鼠的肺动脉高压。
实验结论证实了本发明所涉及的外源性Cyclo(-RGDfK)多肽具有治疗肺动脉高压的作用。
应当指出，以上所述具体实施方式可以使本领域的技术人员更全面地理解本发明，但不以任何方式限制本发明。因此，本领域技术人员应当理解，仍然可以对本发明进行修改或者等同替换；而一切不脱离本发明的精神和技术实质的技术方案及其改进，其均应涵盖在本发明专利的保护范围当中。
Claims (4)
1.Cyclo(-RGDfK)多肽在制备防治肺动脉高压病药物中的应用。
2.Cyclo(-RGDfK)多肽在制备调控Rac1和RhoA的活性的药物中的应用。
3.Cyclo(-RGDfK)在制备抑制肺动脉高压肺动脉平滑肌细胞增殖的药物中的应用。
4.根据权利要求1或2或3所述的应用，所述的药物的剂型为口服制剂或注射剂。
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