CN116617368A - Elabela在抗血管内皮细胞衰老中的应用 - Google Patents
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Abstract
本发明公开Elabela在抗血管内皮细胞衰老中的应用。本发明揭示了Elabela(19‑32)通过抗血管内皮细胞衰老进而延缓血管衰老的作用，为血管衰老的治疗提供了潜在的可应用小分子。本发明动物上以2型糖尿病小鼠血管衰老为模型，在细胞上以用高糖诱导人脐静脉内皮细胞衰老为模型，在动物水平和细胞水平上均发现了Elabela(19‑32)小肽抗血管内皮细胞衰老的作用。
Description
技术领域
本发明属于生命科学技术领域，涉及一种激素肽的肽段在抗血管内皮细胞衰老中的应用，具体涉及Elabela在抗血管内皮细胞衰老中的应用。
背景技术
血管***是维持器官能量代谢平衡的主要通道，目前认为血管老化是机体老化的早期表现和重要病理生理基础之一。内皮细胞衰老被认为是血管老化的重要驱动者，长期的高血糖状态会导致糖尿病患者血管内皮细胞发生衰老，进而导致血管早衰和多种心血管疾病的发生。因此，寻找治疗血管衰老的有效药物对于减少血管老化患者心血管事件的发生具有重要意义。
Elabela是一种激素肽，最早在胚胎干细胞中发现，在胚胎发育过程中具有重要作用。目前被认为是APJ受体的内源性配体之一，Elabela-APJ信号轴已经被证实在心衰、高血压、动脉粥样硬化以及血管新生等心血管疾病中具有重要调控作用。但是Elabela是否可以调控血管内皮细胞衰老还尚不清楚。
发明内容
本发明的第一个目的是针对现有技术的不足，提供Elabela(19-32)小肽在抗血管内皮细胞衰老中的应用。
作为优选，Elabela(19-32)小肽延缓血管内皮细胞衰老，降低血管内皮细胞炎症水平。
作为优选，Elabela(19-32)小肽改善血管硬度。
本发明的第二个目的是提供Elabela(19-32)小肽在制备抗血管内皮细胞衰老药物中的应用。
本发明的第三个目的是提供一种抗血管内皮细胞衰老药物，包含安全有效量的Elabela(19-32)小肽。
作为优选，所述药物还包括药学上可接受的赋形剂或载体。
本发明从临床问题出发，基于糖尿病患者存在血管早衰的现象，构建了2型糖尿病模型小鼠，通过对小鼠的主动脉进行分析证实2型糖尿病小鼠的血管内皮细胞发生了衰老，与糖尿病患者的血管早衰现象具有一致性。进一步，给予Elabela(19-32)腹腔注射(2mg/kg)每天两次，发现Elabela(19-32)能显著改善2型糖尿病小鼠的血管内皮细胞的衰老。细胞上，发现Elabela(19-32)能够剂量依赖性改善高糖诱导的人脐静脉内皮细胞衰老。
本发明的有益效果在于：
本发明首次公开了Elabela(19-32)的抗血管内皮细胞衰老的作用，为血管衰老的治疗提供了潜在的可应用小分子。本发明首次公开了Elabela(19-32)小肽在抗血管内皮细胞衰老中的应用，在动物上以2型糖尿病小鼠血管衰老为模型，在细胞上以用高糖诱导人脐静脉内皮细胞衰老为模型，在动物水平和细胞水平上均发现了Elabela(19-32)小肽抗血管内皮细胞衰老的作用。
附图说明
图1为2型糖尿病小鼠主动脉内皮细胞出现衰老表型，其中A为糖尿病小鼠(T2D)和健康对照小鼠(WT)主动脉内皮细胞的蛋白免疫印迹图，检测了血管炎症相关蛋白vcam1和衰老相关蛋白P16的表达情况；B为A图的统计图，检验方法为：非配对t检验。
图2为Elabela(19-32)改善2型糖尿病小鼠动脉硬化，分别检测了腹腔注射Elabela(19-32)的糖尿病小鼠(T2D-ELA)和腹腔注射PBS的糖尿病小鼠(T2D)的动脉硬化情况，其中A为两组小鼠的左颈动脉脉搏波传导速度(PWV)，B为两组小鼠的左颈动脉血管顺应性，C为为两组小鼠的主动脉脉搏波传导速度(PWV)，D为两组小鼠的主动脉血管顺应性，检验方法为：非配对t检验。
图3为Elabela(19-32)减少2型糖尿病小鼠动脉内皮细胞衰老，检测了腹腔注射Elabela(19-32)的糖尿病小鼠(T2D-ELA)和腹腔注射PBS的糖尿病对照(T2D)的主动脉内皮细胞衰老情况，其中A为两组小鼠内皮细胞的蛋白免疫印迹结果，检测了血管炎症相关蛋白vcam1和衰老相关蛋白P16的表达情况，B为A中P16的统计结果，C为A中vcam1的统计结果，检验方法为：非配对t检验。
图4为Elabela(19-32)减轻高糖诱导的人脐静脉内皮细胞衰老，实验分组为给予高糖诱导内皮细胞衰老之后给予不同剂量的Elabela(19-32)，其中A为细胞SA-β-gal染色代表图，B为A图的统计图，C为蛋白免疫印迹结果，检测了内皮细胞炎症相关蛋白vcam1和衰老相关蛋白P16的表达情况，检验方法为：非配对t检验。
图5为本发明机理流程图。
具体实施方式
下面结合实施例和附图对本发明作进一步的说明，而非限定本发明。
本发明使用小鼠均为C57BL/6J品系，饲养于杭州师范大学实验动物中心无特定病原体(specificpathogenfree，SPF)级动物房。实验所用小鼠均为12周龄雄鼠，所有小鼠实验均遵守国家及杭州师范大学伦理委员会制定的《实验动物使用条例》。使用Vevo3100小鼠超声成像***对实验小鼠的动脉僵硬度进行评估。链脲佐菌素(STZ)购买自Sigma-Aldrich公司；SA-β-gal染色试剂盒购买于上海碧云天生物技术有限公司；60％高脂饲料(D12492)购买于ResearchDiets公司；免疫印迹所用Anti-CDKN2A/p16INK4a抗体(ab211542)购买于abcam公司，Anti-VCAM1Recombinant RabbitMonoclonal抗体(ET1601-18)购买于华安生物；AlphaTubulinMonoclonal抗体(66031-1-Ig)购买于武汉三鹰生物技术有限公司。所有实验结果均包括3次及以上独立实验重复，数据展示形式为平均值±SEM。
本发明所用Elabela(19-32)小肽的氨基酸序列如下：
QRRCMPLHSRVPFP。
实施例1：Elabela(19-32)小肽抗血管内皮细胞衰老作用
基于糖尿病患者存在血管早衰的现象，本实施例利用高脂饮食结合STZ诱导的方式(60％的高脂饮食6周后腹腔注射100mg/kg的STZ之后继续高脂饮食7周)构建了2型糖尿病模型小鼠，提取小鼠主动内皮细胞进行蛋白质免疫印迹发现该模型小鼠出现了血管内皮细胞衰老的表型(图1)。
为了探究Elabela在血管衰老中的作用，本发明体外合成了Elabela的主要活性片段Elabela(19-32)小肽。动物上，在构建2型糖尿病模型的同时通过腹腔注射的方式给予小鼠Elabela(19-32)小肽2mg/kg的每天两次的剂量。与对照PBS相比Elabela(19-32)显著改善了2型糖尿病小鼠的动脉硬度(图2)；进一步分离小鼠主动脉内皮细胞进行免疫印迹检测衰老相关标志物的表达，证明Elabela(19-32)会显著降低主动脉内皮细胞的衰老和炎症水平(图3)。细胞上，给予人脐静脉内皮细胞高糖诱导衰老的同时给予不同剂量的Elabela(19-32)，通过SA-β-gal染色和蛋白免疫印迹实验我们发现Elabela(19-32)会剂量依赖性减轻内皮细胞衰老(图4)。
以上结果表明，Elabela(19-32)可以抗血管内皮细胞衰老进而延缓血管衰老(图5)。
上述实施例并非是对于本发明的限制，本发明并非仅限于上述实施例，只要符合本发明要求，均属于本发明的保护范围。
Claims (6)
1.Elabela(19-32)小肽在抗血管内皮细胞衰老中的应用。
2.根据权利要求1所述应用，其特征在于，Elabela(19-32)小肽延缓血管内皮细胞衰老，降低血管内皮细胞炎症水平。
3.根据权利要求1所述应用，其特征在于，Elabela(19-32)小肽改善血管硬度。
4.Elabela(19-32)小肽在制备抗血管内皮细胞衰老药物中的应用。
5.一种抗血管内皮细胞衰老药物，其特征在于，包含安全有效量的Elabela(19-32)小肽。
6.根据权利要求5所述药物，其特征在于，所述药物还包括药学上可接受的赋形剂或载体。
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| CHAO YE等: "Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects", 《ACTA PHARMACOLOGICA SINICA》, vol. 43, 8 March 2022 (2022-03-08), pages 2573 - 2584 * |
| ZHENG MA等: "Declined ELABELA plasma levels in hypertension patients with atrial fibrillation: a case control study", 《BMC CARDIOVASC DISORD.》, vol. 21, 12 August 2021 (2021-08-12), pages 390 * |
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