AbMole小課堂丨Endothelin-1（ET-1）：一種血管收縮肽，在細(xì)胞和動物實驗中的應(yīng)用Endothelin-1（ET-1，內(nèi)皮素-1，AbMole，M9555）是一種由21個氨基酸組成的強(qiáng)效血管收縮肽，作為內(nèi)皮素家族（包括ET-1、ET-2和ET-3）中的重要成員，ET-1通過其G蛋白偶聯(lián)受體（ETR和ETR）介導(dǎo)多種生物學(xué)效應(yīng)。Endothelin-1在多種動物疾病模型和細(xì)胞實驗中發(fā)揮著重要功能。Endothelin-1（ET-1）的作用機(jī)理Endothelin-1（內(nèi)皮素-1,ET-1，AbMole，M9555）主要通過與其特異性受體的結(jié)合來發(fā)揮生物學(xué)效應(yīng)。目前已知的Endothelin-1受體至少有兩種亞型：ETA受體（ET-RA）和ETB（ET-RB）受體。ETA受體對Endothelin-1具有高度的親和力，主要分布于血管平滑肌細(xì)胞和肝星狀細(xì)胞（hepaticstellatecell,HSC），介導(dǎo)血管收縮和細(xì)胞增殖；而ETB受體對ET-1、ET-2和ET-3的親和力相近，其均勻分布于HSC和竇內(nèi)皮細(xì)胞，參與血管舒張以及抑制細(xì)胞凋亡。Endothelin-1（內(nèi)皮素-1）在與受體結(jié)合后，通過激活G蛋白介導(dǎo)的磷脂酶C-肌醇磷酸途徑，引起細(xì)胞內(nèi)鈣離子濃度升高，進(jìn)而產(chǎn)生一系列生物學(xué)效應(yīng)ADDINEN.CITEADDINEN.CITE.DATA[1]。圖SEQ圖\*ARABIC1.Endothelin-1介導(dǎo)血管收縮的分子機(jī)制ADDINEN.CITE<EndNote><Cite><Author>Banecki</Author><Year>2023</Year><RecNum>965</RecNum><DisplayText><styleface="superscript">[2]</style></DisplayText><record><rec-number>965</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1756705005">965</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Banecki,Kmrm</author><author>Dora,K.A.</author></authors></contributors><auth-address>DepartmentofPharmacology,UniversityofOxford,MansfieldRoad,OxfordOX13QT,UK.</auth-address><titles><title>Endothelin-1inHealthandDisease</title><secondary-title>IntJMolSci</secondary-title><alt-title>Internationaljournalofmolecularsciences</alt-title></titles><periodical><full-title>IntJMolSci</full-title><abbr-1>Internationaljournalofmolecularsciences</abbr-1></periodical><alt-periodical><full-title>IntJMolSci</full-title><abbr-1>Internationaljournalofmolecularsciences</abbr-1></alt-periodical><volume>24</volume><number>14</number><edition>2023/07/29</edition><keywords><keyword>Humans</keyword><keyword>*CardiovascularDiseases/metabolism</keyword><keyword>*COVID-19/metabolism</keyword><keyword>*Endothelin-1/metabolism</keyword><keyword>Endothelins</keyword><keyword>*ChronicPain/metabolism</keyword><keyword>cardiovasculardisease</keyword><keyword>endothelin-1</keyword><keyword>endothelium</keyword><keyword>release</keyword><keyword>storage</keyword><keyword>vasculature</keyword></keywords><dates><year>2023</year><pub-dates><date>Jul10</date></pub-dates></dates><isbn>1422-0067</isbn><accession-num>37511055</accession-num><urls></urls><custom2>PMC10379484</custom2><electronic-resource-num>10.3390/ijms241411295</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[2]Endothelin-1（內(nèi)皮素-1）的科研應(yīng)用Endothelin-1（ET-1）在動物模型中的研究應(yīng)用Endothelin-1（內(nèi)皮素-1,ET-1，AbMole，M9555）在動物模型中的應(yīng)用十分廣泛，覆蓋神經(jīng)、代謝、腎臟、心血管等研究領(lǐng)域，主要機(jī)制包括刺激血管收縮、炎癥激活和纖維化。例如Endothelin-1（內(nèi)皮素-1）在小鼠（C57BL/6J）模型中，可通過側(cè)腦室注射（2μg/2μl）誘導(dǎo)小鼠的血管完整性破壞，以模擬血管性認(rèn)知障礙ADDINEN.CITE<EndNote><Cite><Author>Diwakar</Author><Year>2024</Year><RecNum>949</RecNum><DisplayText><styleface="superscript">[3]</style></DisplayText><record><rec-number>949</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1756693976">949</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Diwakar,Latha</author><author>Gupta,Mayank</author><author>Talukdar,Ankita</author><author>Hussain,Rehab%JAlzheimer's</author><author>Dementia</author></authors></contributors><titles><title>SinglevascularinsultaggravatesamyloidaccumulationwithagetriggeringglialactivationinADmice</title></titles><pages>e092235</pages><volume>20</volume><dates><year>2024</year></dates><isbn>1552-5260</isbn><urls></urls></record></Cite></EndNote>[3]。結(jié)果顯示，Endothelin-1在單次注射后的第3天小鼠出現(xiàn)學(xué)習(xí)和記憶缺陷，但30天后功能有所恢復(fù)。Endothelin-1的注射還可在APPswe轉(zhuǎn)基因小鼠中，誘導(dǎo)血腦屏障結(jié)構(gòu)的改變（內(nèi)皮細(xì)胞和周細(xì)胞標(biāo)記物減少）及Aβ斑塊沉積增加ADDINEN.CITE<EndNote><Cite><Author>Waigi</Author><Year>2024</Year><RecNum>948</RecNum><DisplayText><styleface="superscript">[4]</style></DisplayText><record><rec-number>948</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1756693936">948</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Waigi,EmilyW</author><author>Pernomian,Laena</author><author>Crockett,AlexiaM</author><author>Costa,TiagoJ</author><author>TownsendJr,Paul</author><author>Webb,RClinton</author><author>McQuail,JosephA</author><author>McCarthy,CameronG</author><author>Hollis,Fiona</author><author>Wenceslau,CamillaF%JGeroscience</author></authors></contributors><titles><title>VasculardysfunctionoccurspriortotheonsetofamyloidpathologyandAβplaquedepositscolocalizewithendothelialcellsinthehippocampusoffemaleAPPswe/PSEN1dE9mice</title></titles><pages>5517-5536</pages><volume>46</volume><number>6</number><dates><year>2024</year></dates><isbn>2509-2723</isbn><urls></urls></record></Cite></EndNote>[4]。另外一項研究則是通過構(gòu)建Endothelin-1過表達(dá)的轉(zhuǎn)基因小鼠，建立了實驗性自身免疫性腦脊髓炎（EAE）模型。在該研究中，非轉(zhuǎn)基因小鼠EAE模型（由髓鞘少突膠質(zhì)細(xì)胞糖蛋白/MOG35-55誘導(dǎo)產(chǎn)生的EAE模型）被用作陽性對照。結(jié)果表明，Endothelin-1的過表達(dá)可通過引起巨噬細(xì)胞和脫髓鞘在內(nèi)的炎癥細(xì)胞浸潤增加，誘導(dǎo)實驗動物產(chǎn)生EAEADDINEN.CITE<EndNote><Cite><Author>Guo</Author><Year>2014</Year><RecNum>950</RecNum><DisplayText><styleface="superscript">[5]</style></DisplayText><record><rec-number>950</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1756695521">950</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Guo,Yawei</author><author>Chung,SookjaKim</author><author>Siu,Chung-Wah</author><author>Kwan,Shing-Cheong</author><author>Ho,PhilipWing-Lok</author><author>Yeung,PatrickKa-Kit</author><author>Chan,Koon-Ho%JJournalofneuroimmunology</author></authors></contributors><titles><title>Endothelin-1overexpressionexacerbateexperimentalallergicencephalomyelitis</title></titles><pages>64-70</pages><volume>276</volume><number>1-2</number><dates><year>2014</year></dates><isbn>0165-5728</isbn><urls></urls></record></Cite></EndNote>[5]。在另一項研究中，Endothelin-1被用于SJL/J小鼠的腦內(nèi)注射，發(fā)現(xiàn)Endothelin-1可加劇TMEV病毒誘導(dǎo)的EAE癥狀A(yù)DDINEN.CITEADDINEN.CITE.DATA[6]。Endothelin-1在代謝疾病模型中也有著重要的應(yīng)用。Endothelin-1在C57BL/6J小鼠肥胖模型中（高脂飲食喂養(yǎng)8周）誘導(dǎo)血脂異常、炎癥和胰島素抵抗，而ETB受體基因的敲除可改善小鼠的胰島素敏感性并增加脂聯(lián)素分泌ADDINEN.CITEADDINEN.CITE.DATA[7,8]。Endothelin-1在豬糖尿病模型中（由鏈脲佐菌素/Streptozotocin誘導(dǎo)的糖尿?。?，被證明可通過ROS和ET受體等途徑減少心肌供氧，而ET受體拮抗劑（如Macitentan）可改善上述模型中的微循環(huán)功能ADDINEN.CITEADDINEN.CITE.DATA[9,10]。Endothelin-1在Sprague-Dawley（SD）大鼠中，通過持續(xù)輸注（2pmol/kg/min）激活ETA/ETB受體，增加腎小球通透性，激活下游信號通路（如Rho激酶），導(dǎo)致蛋白尿和腎纖維化ADDINEN.CITEADDINEN.CITE.DATA[11]。Endothelin-1還在多種嚙齒類動物（如自發(fā)性高血壓大鼠）的心血管疾病模型中有著重要應(yīng)用，例如Endothelin-1被發(fā)現(xiàn)可通過血管收縮和重塑促進(jìn)高血壓進(jìn)展ADDINEN.CITEADDINEN.CITE.DATA[12]。Endothelin-1在小鼠胰腺炎模型中（DBTC化學(xué)誘導(dǎo)慢性胰腺炎），通過ETA受體介導(dǎo)傷害性神經(jīng)元敏化，導(dǎo)致持續(xù)性腹部機(jī)械痛覺過敏ADDINEN.CITEADDINEN.CITE.DATA[13]。內(nèi)皮素-1（Endothelin-1,ET-1，AbMole，M9555）在腫瘤的形成和轉(zhuǎn)移過程中發(fā)揮重要作用。例如有研究探索了ET-1在膀胱癌肺轉(zhuǎn)移中的作用。研究使用了裸鼠模型，通過尾靜脈注射UMUC3細(xì)胞，評估了ET-1在腫瘤細(xì)胞與巨噬細(xì)胞之間的通信作用。實驗結(jié)果證明Endothelin-1通過ETAR介導(dǎo)的巨噬細(xì)胞浸潤和炎癥反應(yīng)，促進(jìn)了膀胱癌的肺轉(zhuǎn)移ADDINEN.CITE<EndNote><Cite><Author>Said</Author><Year>2011</Year><RecNum>959</RecNum><DisplayText><styleface="superscript">[14]</style></DisplayText><record><rec-number>959</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1756697900">959</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Said,Neveen</author><author>Smith,Steven</author><author>Sanchez-Carbayo,Marta</author><author>Theodorescu,Dan%JTheJournalofclinicalinvestigation</author></authors></contributors><titles><title>Tumorendothelin-1enhancesmetastaticcolonizationofthelunginmousexenograftmodelsofbladdercancer</title></titles><pages>132-147</pages><volume>121</volume><number>1</number><dates><year>2011</year></dates><isbn>0021-9738</isbn><urls></urls></record></Cite></EndNote>[14]。Endothelin-1（內(nèi)皮素-1）在細(xì)胞實驗中的應(yīng)用Endothelin-1（內(nèi)皮素-1,ET-1，AbMole，M9555）也是細(xì)胞實驗中的重要生物活性分子，其功能涉及細(xì)胞增殖或者纖維化。Endothelin-1可通過結(jié)合其受體ET-AR和ET-BR發(fā)揮促進(jìn)細(xì)胞增殖的作用：例如一項研究發(fā)現(xiàn)，Endothelin-1能夠顯著促進(jìn)人心臟成纖維細(xì)胞的增殖，并通過ET-AR介導(dǎo)合成α-平滑肌肌動蛋白（α-SMA）和膠原蛋白I。使用選擇性ET-AR拮抗劑Ambrisentan可以顯著抑制這些效應(yīng)。Endothelin-1在細(xì)胞纖維化中的作用機(jī)制也得到了深入的研究。Endothelin-1（內(nèi)皮素-1）在C2C12小鼠的成肌細(xì)胞中，能夠誘導(dǎo)細(xì)胞衰老和纖維化。實驗中，細(xì)胞在1nMEndothelin-1處理下表現(xiàn)出顯著的衰老標(biāo)志物增加和纖維化相關(guān)蛋白的表達(dá)。而使用ETAR拮抗劑BQ123和抗氧化劑N-acetylcysteine（NAC）可以抑制上述現(xiàn)象ADDINEN.CITEADDINEN.CITE.DATA[15]。范例詳解SciRep.2025Feb15;15(1):5626.嘉善中醫(yī)院的科研人員在該論文中，探究了內(nèi)皮素轉(zhuǎn)換酶2（ECE2）在NSCLC（非小細(xì)胞肺癌）進(jìn)展中的作用及分子機(jī)制。發(fā)現(xiàn)ECE2作為關(guān)鍵內(nèi)皮素轉(zhuǎn)換酶，可催化Endothelin-1前體轉(zhuǎn)化為成熟的內(nèi)皮素-1（ET-1）。體外實驗中，ECE2過表達(dá)的A549和PC-9細(xì)胞培養(yǎng)上清液中的Endothelin-1水平顯著升高；免疫組化顯示轉(zhuǎn)移組的腫瘤組織中Endothelin-1表達(dá)遠(yuǎn)高于非轉(zhuǎn)移組，且ECE2與Endothelin-1的表達(dá)呈強(qiáng)相關(guān)性，表明ECE2可通過促進(jìn)ET1生成調(diào)控NSCLC的進(jìn)展。在分子機(jī)制上，研究團(tuán)隊發(fā)現(xiàn)Endothelin-1通過YAP1/MAGEA3通路發(fā)揮促腫瘤增殖作用。由AbMole提供的Endothelin-1（內(nèi)皮素-1,ET-1，AbMole，M9555）被實驗人員用于處理A549、PC-9細(xì)胞，結(jié)果顯示兩種細(xì)胞的增殖能力（CCK8assay）和遷移能力（Transwellassay）顯著高于PBS對照組，直接體現(xiàn)Endothelin-1對NSCLC細(xì)胞惡性表型的促進(jìn)作用ADDINEN.CITEADDINEN.CITE.DATA[16]。圖SEQ圖\*ARABIC2.IdentificationofECE2signalinginpromotingnon-smalllungcancerprogressionthroughET1/YAP1/MAGEA3axisADDINEN.CITEADDINEN.CITE.DATA[16]Cytotherapy26(2024)1491-1504中國人民解放軍總醫(yī)院第六醫(yī)學(xué)中心的科研團(tuán)隊在該文章中發(fā)現(xiàn)：神經(jīng)干細(xì)胞的移植可以緩解腦癱大鼠模型（CP）中的運動缺陷。動物實驗表明在移植后的56天，神經(jīng)干細(xì)胞廣泛分布于同側(cè)半球，并分化為神經(jīng)元、少突膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞。移植神經(jīng)干細(xì)胞可增加ET-1處理的腦癱大鼠的BDNF和VEGF表達(dá)，并提高SVZ區(qū)的EdU細(xì)胞數(shù)和RECA-1血管密度，及病灶周圍GAP-43強(qiáng)度。圓柱體測試顯示，從移植28天開始，左前肢運動功能顯著增加，樓梯和Cat-Walk測試顯示精細(xì)運動功能和步態(tài)參數(shù)有所改善。AbMole的Endothelin-1（內(nèi)皮素-1,ET-1，AbMole，M9555）在上述論文中被用于構(gòu)建大鼠的腦癱模型（CP）：在出生后第5天顱內(nèi)給予血管收縮內(nèi)皮素-1（Endothelin-1，ET-1）至大鼠運動皮層和紋狀體，建立CP模型ADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2024</Year><RecNum>963</RecNum><DisplayText><styleface="superscript">[17]</style></DisplayText><record><rec-number>963</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1756703953">963</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,Xiaohua</author><author>Zang,Jing</author><author>Yang,Yinxiang</author><author>Li,Ke</author><author>Ye,Dou</author><author>Wang,Zhaoyan</author><author>Wang,Qian</author><author>Wu,Youjia</author><author>Luan,Zuo</author></authors></contributors><titles><title>Humanneuralstemcellstransplantedduringthesequelaephasealleviatemotordeficitsinaratmodelofcerebralpalsy</title><secondary-title>Cytotherapy</secondary-title></titles><periodical><full-title>Cytotherapy</full-title><abbr-1>Cytotherapy</abbr-1></periodical><pages>1491-1504</pages><volume>26</volume><number>12</number><keywords><keyword>cerebralpalsy</keyword><keyword>motordeficit</keyword><keyword>neuralstemcells</keyword><keyword>neurorepair</keyword><keyword>perinatalstroke</keyword><keyword>sequelaephase</keyword></keywords><dates><year>2024</year><pub-dates><date>2024/12/01/</date></pub-dates></dates><isbn>1465-3249</isbn><urls><related-urls><url>/science/article/pii/S1465324924008041</url></related-urls></urls><electronic-resource-num>/10.1016/j.jcyt.2024.07.012</electronic-resource-num></record></Cite></EndNote>[17]。圖SEQ圖\*ARABIC3.AssessmentofmotorfunctionwithmultiplebehavioraltestsADDINEN.CITE<EndNote><Cite><Author>Wang</Author><Year>2024</Year><RecNum>964</RecNum><DisplayText><styleface="superscript">[17]</style></DisplayText><record><rec-number>964</rec-number><foreign-keys><keyapp="EN"db-id="f2td9w00a22awteprfrp9vaup9d9zwa9tdfr"timestamp="1756704004">964</key></foreign-keys><ref-typename="JournalArticle">17</ref-type><contributors><authors><author>Wang,Xiaohua</author><author>Zang,Jing</author><author>Yang,Yinxiang</author><author>Li,Ke</author><author>Ye,Dou</author><author>Wang,Zhaoyan</author><author>Wang,Qian</author><author>Wu,Youjia</author><author>Luan,Zuo</author></authors></contributors><titles><title>Humanneuralstemcellstransplantedduringthesequelaephasealleviatemotordeficitsinaratmodelofcerebralpalsy</title><secondary-title>Cytotherapy</secondary-title></titles><periodical><full-title>Cytotherapy</full-title><abbr-1>Cytotherapy</abbr-1></periodical><pages>1491-1504</pages><volume>26</volume><number>12</number><keywords><keyword>cerebralpalsy</keyword><keyword>motordeficit</keyword><keyword>neuralstemcells</keyword><keyword>neurorepair</keyword><keyword>perinatalstroke</keyword><keyword>sequelaephase</keyword></keywords><dates><year>2024</year><pub-dates><date>2024/12/01/</date></pub-dates></dates><isbn>1465-3249</isbn><urls><related-urls><url>/science/article/pii/S1465324924008041</url></related-urls></urls><electronic-resource-num>/10.1016/j.jcyt.2024.07.012</electronic-resource-num></record></Cite></EndNote>[17]參考文獻(xiàn)及描述ADDINEN.REFLIST[1]Y.Ji,J.Duan,Q.Yuan,etal.,Structuralbasisofpeptiderecognitionandactivationofendothelinreceptors,NatCommun14(1)(2023)1268.[2]KmrmBanecki,K.A.Dora,Endothelin-1inHealthandDisease,Internationaljournalofmolecularsciences24(14)(2023).[3]LathaDiwakar,MayankGupta,AnkitaTalukdar,etal.,SinglevascularinsultaggravatesamyloidaccumulationwithagetriggeringglialactivationinADmice,20(2024)e092235.[4]EmilyWWaigi,LaenaPernomian,AlexiaMCrockett,etal.,VasculardysfunctionoccurspriortotheonsetofamyloidpathologyandAβplaquedepositscolocalizewithendothelialcellsinthehippocampusoffemaleAPPswe/PSEN1dE9mice,46(6)(2024)5517-5536.[5]YaweiGuo,SookjaKimChung,Chung-WahSiu,etal.,Endothelin-1overexpressionexacerbateexperimentalallergicencephalomyelitis,276(1-2)(2014)64-70.[6]Y.H.Jin,B.Kang,H.S.Kang,etal.,Endothelin-1contributestothedevelopmentofvirus-induceddemyelinatingdisease,Journalofneuroinflammation17(1)(2020)307.[7]O.Rivera-Gonzalez,N.A.Wilson,L.E.Coats,etal.,Endothelinreceptorantagonismimprovesglucosehandling,dyslipidemia,andadiposetissueinflammationinobesemice,Clinicalscience(London,England:1979)135(14)(2021)1773-1789.[8]O.Rivera-Gonzalez,M.F.Mills,B.D.Konadu,etal.,AdipocyteendothelinBreceptoractivationinhibitsadiponectinproductionandcausesinsulinresistanceinobesemice,Actaphysiologica(Oxford,England)240(10)(2024)e14214.[9]R.W.A.vanDrie,J.vandeWouw,L.M.Zandbergen,etal.,Vasodilatorreactiveoxygenspeciesameliorateperturbedmyocardialoxygendeliveryinexercisingswinewithmultiplecomorbidities,Basicresearchincardiology