CN111735968A - Gsdmd作为心肌缺血再灌注损伤的早期诊断标志物的应用 - Google Patents
Gsdmd作为心肌缺血再灌注损伤的早期诊断标志物的应用 Download PDFInfo
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- CN111735968A CN111735968A CN202010787611.0A CN202010787611A CN111735968A CN 111735968 A CN111735968 A CN 111735968A CN 202010787611 A CN202010787611 A CN 202010787611A CN 111735968 A CN111735968 A CN 111735968A
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Abstract
本发明公开了GSDMD作为心肌缺血再灌注损伤的早期诊断标志物的应用，具体公开采用GSDMD制备检测心肌缺血再灌注损伤的诊断试剂或试剂盒。本发明在动物和人水平验证心肌缺血再灌注后GSDMD显著增加，因此可通过检测受试个体外周血或离体心肌组织样品中GSDMD的水平，诊断和预测心肌缺血再灌注损伤，为心肌缺血再灌注损伤的早期诊断提供新的途径。
Description
技术领域
本发明涉及生物医药技术领域，具体地说，涉及GSDMD用于心肌缺血再灌注损伤早期诊断标志物。
背景技术
近年来，随着老龄化社会的来临，人民生活质量的提高及心血管病(Cardiovascular Disease，CVD)危险因素的广泛流行，我国CVD的发病率及死亡率逐年增长。国家心血管中心最新发布的《中国心血管病报告2016》中指出，我国目前CVD死亡占城乡居民总死亡原因的首位，农村为45.01％，城市为42.61％，高于肿瘤及其他系统疾病(图1)。其中，缺血性心脏病(Ischemic Heart Disease，IHD)尤其是冠心病(Coronary HeartDisease，CHD)是导致CVD死亡的首要病因。而急性心肌梗死(Acute MyocardialInfarction，AMI)则是导致冠心病死亡的主要原因。近年来，随着药物及器械治疗的发展以及全国各地区多条急性心梗绿色通道的共同努力，急性心梗的罪犯血管得到了早期、及时的开通，使得AMI死亡率大大降低。然而，罪犯血管供血范围内的缺血心肌再灌注后会发生组织细胞代谢功能障碍及结构破坏进一步加重的现象，即心肌缺血/再灌注损伤(Myocardial Ischemia/Reperfusion Injury，MIRI)。MIRI导致缺血心肌的坏死范围扩大，心肌组织纤维化加重，心脏的负性重塑导致心功能下降，最终发展为心衰(Heart Failure，HF)。HF的发生导致急性心梗患者的远期生活质量大大降低。因此，如何有效地诊断及治疗罪犯血管开通后的MIRI是降低AMI死亡率及提高患者远期生活治疗亟待解决的问题。
研究表明，GSDMD(Gasdermin D，又称DF5L、DFNA5L、FKSG10和GSDMDC1，位点NC_000008.11)蛋白能够在胞质内脂多糖(Lipopolysaccharide，LPS)等刺激下被caspase-1/4/5/11等切割产生N端和C端残基，其中N端能够形成寡聚体，在细胞膜上形成穿膜孔道，诱发细胞的炎症性死亡，即为焦亡。目前关于GSDMD和细胞焦亡的研究主要集中于免疫相关的巨噬细胞和中性粒细胞等，在心肌细胞中的表达和作用尚无相关报道，关于GSDMD在心脏缺血再灌注中的作用也缺少相关研究结果证实。
发明内容
本发明的第一个目的是针对现有技术中的不足，提供GSDMD或其检测试剂的用途。
本发明的第二个目的是针对现有技术中的不足，提供一种检测心肌缺血再灌注损伤的诊断试剂盒。
本发明采取的技术方案是：
GSDMD或其检测试剂的用途，用于制备检测心肌缺血再灌注损伤的诊断试剂或试剂盒。
作为本发明的一个优选实施方案，所述GSDMD来源于人体外周血(AK291817)，其氨基酸序列为MGSAFERVVRRVVQELDHGGEFIPVTSLQSSTGFQPYCLVVRKPSSSWFWKPRYKCVNLSIKDILEPDAAEPDVQRGRSFHFYDAMDGQIQGSVELAAPGQAKIAGGAAVSDSSSTSMNVYSLSVDPNTWQTLLHERHLRQPEHKVLQQLRSRGDNVYVVTEVLQTQKEVEVTRTHKREGSGRFSLPGATCLQGEGQGHLSQKKTVTIPSGSTLAFRVAQLVIDSDLDVLLFPDKKQRTFQPPATGHKRSTSEGAWPQLPSGLSMMRCLHNFLTDGVPAEGAFTEDFQGLRAEVETISKELELLDRELCQLLLEGLEGVLRDQLALRALEEALEQGQSLGPVEPLDGPAGAVLECLVLSSGMLVPELAIPVVYLLGALTMLSETQHKLLAEALESQTLLGPLELVGSLLEQSAPWQERSTMSLPPGLLGNSWGEGAPAWVLLDECGLELGEDTPHVCWEPQAQGRMCALYASLALLSGLSQEPH(如SEQ ID NO:1所示)。
作为本发明的一个优选实施方案，所述检测是指受试个体外周血检测。
作为本发明的一个优选实施方案，所述检测是指离体心肌组织样品检测。
作为本发明的一个优选实施方案，GSDMD检测试剂是GSDMD的特异性抗体。
为实现上述第二个目的，本发明采取的技术方案是：
一种检测心肌缺血再灌注损伤的诊断试剂盒，所述试剂盒包含检测GSDMD表达的试剂。
作为本发明的一个优选实施方案，所述检测GSDMD表达的试剂是GSDMD的特异性抗体。
作为本发明的一个优选实施方案，所述检测是指受试个体外周血检测或离体心肌组织样品检测。
本发明还提供GSDMD的用途，它被用作心肌缺血再灌注损伤的早期诊断标志物。
本发明通过western blot，免疫荧光和ELISA等实验发现，在心肌缺血再灌注后，GSDMD及其活性形式GSDMD-N的生成显著增加。
通过细胞实验，我们发现GSDMD能够分泌到细胞外。
通过人体试验，发现缺血再灌注损伤后GSDMD水平显著升高。
本发明在动物和人体水平验证心肌缺血再灌注后GSDMD显著增加，因此可通过检测受试个体外周血或离体心肌组织样品中GSDMD的水平，诊断和预示心肌缺血再灌注损伤，为心肌缺血再灌注损伤的早期诊断提供新的途径。
附图说明
图1为《中国心血管报告2016》公布的城乡死亡构成比。
图2为Western Blot实验结果；显示：C57小鼠心肌缺血再灌注后3小时及34小时GSDMD的水平，在心肌缺血再灌注后，GSDMD的生成显著增加。
图3为免疫荧光实验结果；显示：C57小鼠缺血再灌注后24小时心肌组织中GSDMD显著增加，在心肌缺血再灌注后，GSDMD的生成显著增加。
图4为心肌细胞在氧化应激条件下向外周培养基分泌的GSDMD水平，显示：GSDMD水平显著增加。
图5为人的缺血性心肌组织中GSDMD的表达水平，以及PCI术后缺血再灌注不同时间点血清中GSDMD的水平。
具体实施方式
下面结合具体实施方式，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明记载的内容之后，本领域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。
以下实施例中采用的技术路线是：
1)对野生型C57小鼠以及GSDMD基因敲除小鼠进行缺血再灌注损伤模型建立，分别取小鼠再灌注后3小时、24小时和48小时的血清及心肌组织。通过ELISA，WB和免疫荧光等技术检测心肌缺血再灌注损伤后小鼠外周血及心肌组织中的GSDMD的水平。结果发现，野生型C57小鼠心肌缺血再灌注损伤后GSDMD的水平较假手术组显著升高。
2)验证GSDMD在心肌缺血再灌注损伤中的作用，建立心肌缺血再灌注损伤模型后，通过心超和染色的方法检测GSDMD对小鼠心功能和梗死面积的影响。结果发现，GSDMD基因敲除小鼠在缺血再灌注模型后心功能和梗死面积显著优于野生型C57小鼠。
3)检测在心肌细胞在氧化应激条件下向外周培养基分泌的GSDMD水平。结果发现，GSDMD在心肌细胞发生焦亡时可分泌到细胞外。
4)收集病人标本，以及PCI术后发生缺血性再灌注不同点的外周血，检测缺血性心肌组织中GSDMD的表达水平，血清中GSDMD的水平。结果发现，组织和外周血中GSDMD的水平显著升高。
实施例1
建立小鼠缺血再灌注损伤模型及检测GSDMD的水平，具体操作如下：
(1)小鼠缺血再灌注损伤模型的建立：小鼠使用2％异氟烷麻醉后，胸前区脱毛，75％酒精消毒，铺巾，在X肋处开一Xmm小口，钝性分离肌肉，撑开肋骨后挤出心脏，6-0丝线在左心耳下方Xmm处结扎冠脉，打一活结，4-0丝线缝合切口，心电图检查心脏是否缺血，40min后松开活结，心电图观察是否再灌注。
(2)GSDMD水平的检测，具体为：
Western blot：小鼠心脏样品取下后在液氮中冻存，24h后转移到-80摄氏度保存。组织剪碎后，加入RIPA裂解液，超声破碎细胞后裂解30min，4度12000g离心30min后取上清，加入SDS-PAGE loading buffer 95度煮样5min。
细胞样品弃去培养基后，加入SDS裂解液刮下细胞，收集液体后加入SDS-PAGEloading buffer 95度煮样20min。蛋白样品加入12-15％的SDS凝胶中电泳，采用湿转方法转膜到PVDF膜上。5％BSA-TBST中封闭2h，一抗4度过夜，TBST洗膜3次后二抗室温孵育2h。
ELISA：按试剂生产商所给的实验流程操作。小鼠麻醉后眼球取血，室温凝固30min后4度3000g离心15min，吸取血清-80度冻存。
免疫荧光：样品在OCT中包埋后，在冰冻切片机上切片，4％多聚甲醛固定10min，PBS清洗3次，0.5％Triton X-100破膜10min，PBS清洗3次；5％BSA-PBS封闭1h，4度湿盒中一抗孵育过夜。PBS清洗3次后，二抗常温孵育1h，DAPI孵育10min，PBS清洗3次后共聚焦显微镜拍摄。
通过上述western blot，免疫荧光和ELISA等实验发现，在心肌缺血再灌注后，GSDMD及其活性形式GSDMD-N的生成显著增加(图2，图3，图4)。
通过细胞实验，心肌细胞在氧化应激条件下，GSDMD能够分泌到细胞外，与对照组相比，氧化应激组外周细胞培养液中GSDMD水平显著增加(图4)。
通过人体试验，通过心肌细胞定位证实，人体心肌细胞中大量表达GSDMD蛋白，同时人体心脏在发现缺血再灌注损伤后，心肌细胞释放大量GSDMD，发生心脏缺血再灌注损伤的病人外周血液GSDMD水平显著升高(图5)。
上述实施例证明，在动物和人体水平验证心肌缺血再灌注后GSDMD显著增加，因此可通过检测受试个体外周血或离体心肌组织样品中GSDMD的水平，诊断和预示心肌缺血再灌注损伤。
上述对实施例的描述是为了便于该技术领域的普通技术人员能理解和使用本发明。熟悉本领域技术人员显然可以容易的对这些实施例做出各种修改，并把在此说明的一般原理应用到其他实施例中，而不必经过创造性的劳动。因此，本发明不限于上述实施例。本领域技术人员根据本发明的原理，不脱离本发明的范畴所做出的改进和修改都应该在本发明的保护范围之内。
序列表
<110> 复旦大学附属中山医院
<120> GSDMD作为心肌缺血再灌注损伤的早期诊断标志物的应用
<141> 2020-08-07
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Arg Asp Gln Leu Ala Leu Arg Ala Leu Glu Glu Ala Leu Glu Gln Gly
325 330 335
Gln Ser Leu Gly Pro Val Glu Pro Leu Asp Gly Pro Ala Gly Ala Val
340 345 350
Leu Glu Cys Leu Val Leu Ser Ser Gly Met Leu Val Pro Glu Leu Ala
355 360 365
Ile Pro Val Val Tyr Leu Leu Gly Ala Leu Thr Met Leu Ser Glu Thr
370 375 380
Gln His Lys Leu Leu Ala Glu Ala Leu Glu Ser Gln Thr Leu Leu Gly
385 390 395 400
Pro Leu Glu Leu Val Gly Ser Leu Leu Glu Gln Ser Ala Pro Trp Gln
405 410 415
Glu Arg Ser Thr Met Ser Leu Pro Pro Gly Leu Leu Gly Asn Ser Trp
420 425 430
Gly Glu Gly Ala Pro Ala Trp Val Leu Leu Asp Glu Cys Gly Leu Glu
435 440 445
Leu Gly Glu Asp Thr Pro His Val Cys Trp Glu Pro Gln Ala Gln Gly
450 455 460
Arg Met Cys Ala Leu Tyr Ala Ser Leu Ala Leu Leu Ser Gly Leu Ser
465 470 475 480
Gln Glu Pro His
Claims (9)
1.GSDMD或其检测试剂的用途，其特征在于，用于制备检测心肌缺血再灌注损伤的诊断试剂或试剂盒。
2.根据权利要求1所述的用途，其特征在于，所述GSDMD来源于人体外周血，其氨基酸序列如SEQ ID NO:1所示。
3.根据权利要求1所述的用途，其特征在于，所述检测是指受试个体外周血检测。
4.根据权利要求1所述的用途，其特征在于，所述检测是指离体心肌组织样品检测。
5.根据权利要求1所述的用途，其特征在于，GSDMD检测试剂是GSDMD的特异性抗体。
6.一种检测心肌缺血再灌注损伤的诊断试剂盒，其特征在于，所述试剂盒包含检测GSDMD表达的试剂。
7.根据权利要求6所述的试剂盒，其特征在于，所述检测GSDMD表达的试剂是GSDMD的特异性抗体。
8.根据权利要求6所述的试剂盒，其特征在于，所述检测是指受试个体外周血检测或离体心肌组织样品检测。
9.GSDMD的用途，其特征在于，它被用作心肌缺血再灌注损伤的早期诊断标志物。
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| CN113109569A (zh) * | 2021-03-05 | 2021-07-13 | 李朴 | Gsdmd作为生物标志物在胸腔积液相关疾病鉴别诊断及疗效评估上的用途 |
| CN113462653A (zh) * | 2021-07-05 | 2021-10-01 | 东北农业大学 | 抗猪Gasdermin D蛋白单克隆抗体、分泌该单克隆抗体杂交瘤细胞株及其应用 |
| CN115819548A (zh) * | 2021-11-16 | 2023-03-21 | 北京美德泰康生物科技有限公司 | 一种检测炎症相关疾病的标志物和方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113109569A (zh) * | 2021-03-05 | 2021-07-13 | 李朴 | Gsdmd作为生物标志物在胸腔积液相关疾病鉴别诊断及疗效评估上的用途 |
| CN113462653A (zh) * | 2021-07-05 | 2021-10-01 | 东北农业大学 | 抗猪Gasdermin D蛋白单克隆抗体、分泌该单克隆抗体杂交瘤细胞株及其应用 |
| CN115819548A (zh) * | 2021-11-16 | 2023-03-21 | 北京美德泰康生物科技有限公司 | 一种检测炎症相关疾病的标志物和方法 |
| CN115819548B (zh) * | 2021-11-16 | 2023-09-01 | 北京美德泰康生物科技有限公司 | 一种检测炎症相关疾病的标志物和方法 |
| WO2024103504A1 (zh) * | 2021-11-16 | 2024-05-23 | 北京美德泰康生物科技有限公司 | 一种检测炎症相关疾病的标志物和方法 |
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