CN104198697A - 离心力和剪应力应答基因1（recs1）在治疗血管损伤后再狭窄中的功能和应用 - Google Patents
离心力和剪应力应答基因1（recs1）在治疗血管损伤后再狭窄中的功能和应用 Download PDFInfo
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- CN104198697A CN104198697A CN201410411027.XA CN201410411027A CN104198697A CN 104198697 A CN104198697 A CN 104198697A CN 201410411027 A CN201410411027 A CN 201410411027A CN 104198697 A CN104198697 A CN 104198697A
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Abstract
本发明公开了一种离心力和剪应力应答基因1（RECS1）在治疗血管损伤后再狭窄中的功能和应用。本发明以RECS1基因敲除小鼠和野生型小鼠为实验对象，通过血管损伤模型，进行了小鼠内膜新生、血管壁细胞增殖水平和平滑肌细胞表型转换的检测。结果表明，RECS1基因敲除可以明显抑制内膜新生和细胞增殖，抑制平滑肌细胞由收缩型向合成型转换。这表明RECS1在血管损伤后再狭窄中的功能主要体现为RECS1可以促进内膜新生和细胞增殖及平滑肌细胞表型转换。针对RECS1的功能，其可作为药物靶标用于筛选预防、缓解和/治疗血管损伤后再狭窄疾病的药物，其抑制剂可用于制备预防、缓解和/治疗血管损伤后再狭窄的药物和动脉支架。
Description
技术领域
本发明属于基因的功能与应用领域，具体涉及一种离心力和剪应力应答基因1（responsive to centrifugal force and shear stress gene 1，RECS1）在治疗血管损伤后再狭窄中的功能和应用，具体是RECS1在制备预防、缓解和/或治疗血管损伤后再狭窄的药物中的应用。
背景技术
随着饮食结构的变化和人口的老龄化进程，动脉粥样硬化闭塞性病变呈现逐年增高的趋势并成为我们国家主要的致死原因之一。新生内膜形成是动脉粥样硬化（atherosclerosis，AS）、肺动脉高压、经皮冠状动脉介入治疗（percutaneous transluminal coronary intervention，PCI）术后再狭窄（RS）、移植后动脉病以及肺动脉高压等血管增生性疾病共有的病理过程。血管的内膜新生是血管在各种损伤因素刺激下发生的病理改变，是多种心血管系统疾病共有的病理过程。血管平滑肌细胞（vascular smooth muscle cells，VSMCs）表型转化在新生内膜形成过程中扮演着重要的角色。血管损伤后，血管平滑肌细胞由中膜向内膜迁移，平滑肌细胞的增殖凋亡失平衡，表型由收缩型向合成型转变，血管壁不适重塑，从而引起内膜增生。对这类疾病目前尚无根治方法，血管外科的主要治疗手段是闭塞段血管重建，包括球囊扩张、支架置入以及动脉旁路手术等，虽然可以实现血管重建，有效的疏通阻塞的动脉，改善血供，但是血管重建后再狭窄的发生率较高（30～60%），极大地影响了治疗效果，迄今为止血管重建后再狭窄依然是一个临床难题。
肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）是一个多功能细胞因子，它是细胞凋亡、炎症和免疫的主要调节因子，它和细胞膜上的特异性的受体结合后发挥促进细胞生长、分化、凋亡及诱发炎症等重要作用。TNF-α信号失调与人类一系列疾病密切相关，包括败血症、糖尿病、癌症、骨质疏松以及动脉粥样硬化等【1】。TNF-α通过激活细胞内炎症相关的信号通路尤其是NF-κB通路而诱导细胞表达各种炎症标志物，在血管损伤局部浸润的炎性细胞，通过分泌TNF-α而诱导VSMC表型转化和增殖。已有研究报道TNF-α自身及其诱导表达的蛋白与VSMC增殖和迁移的过程密切相关【2, 3】。
RECS1（responsive to centrifugal force and shear stress gene 1）是血液剪切力应答蛋白。Nojima实验室【4】最早报道血液剪应力诱导RECS1的转录表达，并克隆得到RECS1的cDNA和氨基酸序列。人RECS1是1个有311个氨基酸的7次跨膜蛋白，与Lifeguard和谷氨酸结合蛋白具有很高的同源性。RECS1基因敲除的小鼠年老时易患主动脉囊性中层坏死并表现有大动脉扩张症，表明RECS1可能参与调控血管的发育重塑【5】。RECS1是肿瘤坏死因子受体2（tumor neucrosisfactor receptor 2，TNFR2）的结合蛋白质，有报道表明稳定表达RECS1的小鼠成纤维细胞对TNFR2特异的激动性抗体表现出一定的耐受性，表明RECS1可能参与TNF-α信号的调控【6】。近期的研究结果显示，RECS1结合TNFR1，并抑制过量表达TNFR1诱导的核转录因子-κB（NF-κB）活化，从而负调控TNF-α信号【7】。由此推测RECS1基因的表达可能通过调节TNF-α信号通路，从而影响血管VSMC的功能。
【参考文献】
1、Barzilay JI, Abraham L, Heckbert SR, et al. The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. Diabetes.2001, 50(10):2384-9.
2、Yoshida S, Ono M, Shono T, et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Molecular and Cellular Biology, 1997, 17:4015-4023.
3、Lee SJ, Kim WJ, Moon SK. TNF-α regulates vascular smooth muscle cell responses in genetic hypertension. International Immunopharmacology, 2009; 9:837-843.
4、H.Yoshisue，K.Suzuki，A.Kawabatal, Atherosclerosis 162，323(Jun, 2002).
5、Zhao H1, Ito A, Sakai N, Matsuzawa Y, et al. RECS1 is a negative regulator of matrix metalloproteinase-9 production and aged RECS1 knockout mice are prone to aortic dilation. Circ J. 2006 May;70(5):615-24.
6、蔡慈峰，吴明江，廖志勇．中国生物化学与分子生物学报26，36（Jan, 2010）。
7、廖志勇．中国生物化学与分子生物学报27，412（May, 2011）。
发明内容
为解决上述现有技术的缺陷和不足，本发明的目的在于确定RECS1的表达和血管损伤后再狭窄的相互关系，提供一种RECS1作为药物靶标在筛选预防、缓解和/治疗血管损伤后再狭窄的药物中的应用，提供一个用于预防、缓解和/或治疗血管损伤后再狭窄的靶基因RECS1的新用途。
本发明的目的通过下述技术方案实现：
本发明以野生型C57BL/6小鼠与RECS1基因敲除小鼠（RECS1-KO小鼠）为实验对象，通过颈动脉导丝损伤模型诱导获得小鼠血管损伤模型（vascular injury，VI），进行了血管损伤模型（VI）小鼠内膜新生测定、血管壁细胞增殖水平的检测和平滑肌细胞表型的检测的研究，结果表明：与野生型C57BL/6小鼠对比，RECS1基因敲除小鼠表现出内膜新生及细胞增殖明显低于WT小鼠；RECS1基因敲除可以抑制细胞增殖核抗原（Proliferating Cell Nuclear Antigen，PCNA）和细胞周期蛋白（Cyclin D1）的表达，可抑制平滑肌细胞的增殖和内膜增生；RECS1基因敲除可以促进平滑肌肌动蛋白（Smooth Muscle Actin，SMA）和平滑肌22α（smooth muscle 22 alpha，SM22α）的表达，可抑制平滑肌细胞由收缩型向合成型的表型转换，从而抑制内膜增生。上述结果表明RECS1基因敲除会减少血管损伤后再狭窄的发生，RECS1能够促进血管损伤后再狭窄的形成，为研究预防、缓解和/或治疗血管损伤后再狭窄的新靶点和新策略提供了理论依据和临床基础。
因此，RECS1基因可作为药物靶点，构建RECS1基因过表达的体外细胞模型或动物模型，用于筛选预防、缓解和/或治疗血管损伤后再狭窄的药物；RECS1基因也可作为基因治疗中的靶基因，设计并制备预防、缓解和/或治疗血管损伤后再狭窄的药物和/或生物学试剂，通过基因工程技术达到预防、缓解和/或治疗血管损伤后再狭窄的目的。例如以RECS1为靶基因，设计可干扰RECS1表达的双链siRNA，通过化学方法合成以后，注射入人体通过RNA干扰的方法使RECS1基因沉默来治疗血管损伤后再狭窄；还可以设计并构建RECS1的突变体，注射后进入细胞，竞争RECS1原形的作用底物，从而抑制RECS1的功能，起到治疗目的；此外，还可以以RECS1为靶点设计小分子化合物抑制剂，利用RECS1基因过表达的体外细胞模型或动物模型，通过筛选，发现其中能够特异性抑制RECS1的分子，从而为血管损伤后再狭窄的治疗提供新的治疗性分子。
针对RECS1的上述功能，提供RECS1作为药物靶标在筛选预防、缓解和/或治疗血管损伤后再狭窄的药物中的应用。
针对RECS1的上述功能，提供RECS1的抑制剂在制备预防、缓解和/或治疗血管损伤后再狭窄的药物中的应用。
一种预防、缓解和/或治疗血管损伤后再狭窄的药物，包含RECS1的抑制剂。
一种预防、缓解和/或治疗血管损伤后再狭窄的动脉支架，其包被有RECS1的抑制剂。
所述的RECS1的抑制剂优选为RECS1基因的siRNA、RECS1基因的RNA干扰载体，RECS1的抗体及其他能够抑制RECS1表达的抑制剂中的一种。
在本发明中，所述血管损伤主要是指动脉血管损伤。
在本发明中，所述血管损伤是指动脉粥样硬化引起的血管损伤，或者在治疗动脉粥样硬化时引起的血管损伤，例如通过球囊扩张或放入支架引起的血管损伤，或者移植后动脉病或肺动脉高压引起的血管损伤。
在本发明中，所述动脉粥样硬化既包括动脉粥样硬化较早期阶段的血管狭窄期，也包括动脉粥样硬化严重时的血管梗塞期。
在本发明中，所述经皮冠状动脉介入治疗是指经导管通过各种方法扩张狭窄的冠状动脉，从而达到解除狭窄，改善心肌血供的治疗方法。
在本发明中，所述动脉支架是指用于支撑人体内因病变而狭窄、闭塞的血管，恢复血液流通的管状器件，采用金属或高分子材料加工制成，可长期或暂时留于人体血管内。在管腔球囊扩张成形的基础上，在病变段置入支架以达到支撑狭窄闭塞段血管、减少血管弹性回缩及再塑形、保持管腔血流通畅的目的，既包括外周动脉支架，也包括冠状动脉支架。
在本发明中，所述再狭窄是指在局部血管发生损伤时，所作出的导致血管管腔再狭窄的普遍性生物学反应。这里主要指医源性损伤引起的血管再狭窄，损伤过程主要由动脉重塑和内皮增生组成。
本发明相对于现有技术具有如下的优点及效果：
（1）本发明发现了RECS1基因的新功能，即RECS1能够促进血管损伤后再狭窄的作用。
（2）基于RECS1在促进血管损伤后再狭窄的功能，为研制血管损伤后再狭窄的药物提供了靶标。
（3）RECS1的抑制剂可用于制备预防、缓解和/或治疗血管损伤后再狭窄的药物。
（4）RECS1的抑制剂可用于制备预防、缓解和/或治疗血管损伤后再狭窄的动脉支架。
附图说明
图1是WT和RECS1-KO小鼠术后28天的HE染色及内膜面积结果统计柱状图；其中，A：HE染色图，B：内膜面积统计柱状图（*：p＜0.05 vs WT VI组）。
图2是WT和RECS1-KO小鼠术后28天血管壁细胞增殖水平标志物PCNA、CyclinD1表达的免疫荧光染色及结果统计柱状图；其中，A：免疫荧光染色，B：结果统计柱状图（*：p＜0.05 vs WT VI组）。
图3是WT和RECS1-KO小鼠术后28天平滑肌细胞表型转换标志物SMA、SM22α表达的免疫荧光染色及结果统计柱状图；其中，A：免疫荧光染色，B：柱状图（*：p＜0.05 vs WT VI组）。
具体实施方式
下面结合具体实施例和附图对本发明做进一步详细的描述。应理解，下面的实施例仅用于说明本发明而不用于限制本发明的范围。
实验用动物及饲养
实验动物：选用8-10周龄、体重在24-27g，雄性，C57BL/6小鼠（WT小鼠，购自北京华阜康生物科技有限公司）和RECS1基因敲除小鼠（RECS1-KO，购自日本RIKEN公司，货号：RBRC01772）。
饲养环境：所有实验小鼠均饲养在武汉大学心血管病研究所SPF级实验动物中心。SPF级大小鼠饲料购自北京华阜康生物科技有限公司，饲养条件：室温在22-24℃之间，湿度在40-70%之间，明暗交替照明时间为12h，自由饮水摄食。
实施例1 小鼠血管损伤模型（VI）获得
1. 实验动物分组：使用8-10周龄，体重24-27g的WT和RECS1-KO小鼠，共分为2组：WT血管损伤组，RECS1-KO血管损伤组，每组各20只小鼠。分别在手术后28天处死小鼠，取损伤节段血管进行分析。
2. 小鼠血管损伤模型操作流程：
1）用电子天平于动态模式下准确称取小鼠体重（g），用双蒸水准确配置3%戊巴比妥钠溶液，轻轻摇动使其充分溶解，采用80mg/kg体重剂量，计算所需戊巴比妥钠溶液体积后用1mL注射器准确抽取相应体积溶液，行腹腔注射麻醉小鼠，待小鼠充分麻醉倒（约3min）后，8%硫化钠颈部脱毛。
2）分离颈内和颈外动脉。
3）在颈内动脉和颈外动脉分叉处用8-0线结扎颈外动脉，同时用血管夹（WPI, 501784-G）暂时性阻断颈内动脉及颈总动脉供血。
4）用显微剪（WPI, 501839）在颈外动脉结扎线的上方横向剪一个小口。经此血管切口插入直径0.015英寸的导丝（No. C-SF-15-15, Cook, Bloomington, Indiana），旋转导丝进退5-6次。
5）在切口近心端结扎颈外动脉，松开颈内及颈总动脉置留的血管夹，剪断线头，清理术野，缝合颈部切口。
实施例2 血管损伤模型（VI）小鼠内膜新生测定
1. 小鼠取材
1）麻醉小鼠，剪破心脏放血。
2）从颈动脉近分叉处剪下颈动脉，取0.5-0.6cm长，保留颈外动脉线结。
3）将颈动脉放入PBS中，用显微镊轻柔排干管腔内的残血。
4）将血管放入装有1mL 4%多聚甲醛的1.5mL EP管中固定。
2. 病理学检测
2.1 制备石蜡标本切片
由实验室专业病理工作人员制备石蜡标本切片，主要操作程序包括：4%多聚甲醛中隔夜固定后，将血管用滤纸小心包好，放入包埋框→流水冲洗→脱水→透明→浸蜡→包埋→切片（3μm）→摊片→晾干或烘烤后备用。
2.2 苏木精-伊红（HE）染色
主要步骤为：55℃烘烤30min→二甲苯5min，3次→100%酒精1min→95%酒精1min→70%酒精1min→双蒸水1min→苏木素溶液（珠海贝索，BA-4021）5min→水洗1min→1%盐酸酒精（取3mL浓盐酸与297mL 70%酒精充分混合均匀）1-3s→水洗1min→Scott液（碳酸氢钠0.35g，硫酸镁2g，蒸馏水100mL）1min→水洗1min→伊红溶液（珠海贝索，BA-4024）3-5min→蒸馏水洗去浮色→70%酒精1s→95%酒精1s→100%酒精30s，3次→二甲苯2min，3次→趁二甲苯未干立即封片→通风橱内吹干，显微镜拍照。
以血管内弹力纤维和外弹力纤维为界，内弹力板以内为血管内膜，外弹力板以外为血管外膜，内外弹力板之间为血管中膜。用Image-Pro Plus 6.0软件分别圈各血管管腔面积。
内膜面积大小的计算参照公式如下：
新生内膜面积=内弹力板面积-管腔面积；
中膜面积=外弹力板面积-内弹力板面积。
小鼠HE染色后的血管内膜新生的结果如图1。正常的血管壁结构完整，排列整齐，血管内膜为单层内皮细胞，结构完整，中膜平滑肌细胞排列整齐。通过HE染色观察到，血管损伤组（VI组）血管壁结构不完整，血管内皮细胞缺失，新生内膜增生明显，并伴有大量炎细胞浸润；RECS1-KO组在术后28天新生内膜面积明显比WT小鼠要低。同样，内膜面积/中膜面积的比值在VI术后RECS1-KO组要低于WT组。这说明RECS1基因的缺失可以抑制血管损伤后引起的内膜新生。
实施例3 血管壁细胞增殖水平的检测
免疫荧光染色检测细胞增殖核抗原（Proliferating Cell Nuclear Antigen，PCNA）、细胞周期蛋白（Cyclin D1）的表达。所需一抗信息：PCNA（#2586; 1:100; mouse; Cell Signaling Technology），cyclin D1（#2978; 1:25; rabbit; Cell Signaling Technology）；所需二抗信息：Alexa Fluor 568-conjugated goat anti-rabbit IgG（A11011; Invitrogen, Carlsbad, CA），Alexa Fluor 568-conjugated goat anti-mouse IgG（A11004; Invitrogen, Carlsbad, 150 d, CA）。
主要步骤为：
1）烤片：将石蜡切片置于55℃烤箱中30min以上。
2）脱蜡：二甲苯5min×3。
3）水合：100%乙醇5min×2；95%乙醇5min；70%乙醇5min；ddH2O浸洗5min×2。
4）柠檬酸盐组织抗原修复（高压修复）：取一定量的pH6.0柠檬酸盐抗原修复工作液（购自福州迈新生物科技有限公司，货号 MVS-0100）于修复盒中，修复工作液的量必须能足够浸没整张切片，将修复盒放入已加入适量自来水的高压锅中，大火加热至沸腾，将脱蜡水合后的组织切片置于耐高温染色架上，再将染色架缓慢放入修复盒中，盖上锅盖，扣上压力阀，继续加热至喷气，开始计时5min后，压力锅断开电源，去阀开盖，取出修复盒；室温放置20min自然冷却后取出切片。
5）ddH2O漂洗5min×2次，PBS漂洗5min×2次。
6）组化笔划圈，滴加10%羊血清（GTX27481，GeneTex）封闭，于湿盒中37℃封闭60min。
7）弃封闭液，滴加适当比例稀释的一抗，4℃孵育过夜，37℃复温30min，弃去一抗，PBS洗10min×3次。
8）滴加二抗，于湿盒中37℃孵育60min，弃去二抗，PBS浸洗5min×3次。
9）SlowFade Gold antifade reagent with DAPI（S36939，Invitrogen）封片。
10）荧光镜下观察，拍照。若需保存，于暗湿盒中4℃保存。
荧光统计方法：PCNA免疫荧光染色统计采用IPP软件计数，PCNA阳性细胞百分比=PCNA阳性细胞个数/（内膜+中膜）的总DAPI个数*100%；CyclinD1免疫荧光染色统计采用IPP软件直接测阳性吸光度。
免疫荧光法观察平滑肌细胞增殖标志物PCNA、CyclinD1在WT和RECS1-KO小鼠血管损伤后的表达变化，结果见图2。PCNA、CyclinD1在血管组织中有表达，RECS1-KO小鼠在术后28天PCNA的阳性细胞个数及CyclinD1的荧光强度均要小于同组的WT小鼠，表明RECS1基因敲除可以抑制PCNA、CyclinD1的表达，可抑制平滑肌细胞的增殖和血管内膜新生。
实施例4 平滑肌细胞表型的检测
免疫荧光染色检测平滑肌细胞分化标志物：平滑肌肌动蛋白（Smooth Muscle Actin，SMA）、平滑肌22α（smooth muscle 22 alpha，SM22α）的表达。所需一抗信息：SMA（ab5694; 1:100; rabbit; Abcam）and SM22α（ab14106; 1:100; rabbit; Abcam）；所需二抗信息：Alexa Fluor 488-conjugated goat anti-rabbit IgG（A11008; Invitrogen, Carlsbad, CA）。
主要步骤参照实施例3。
荧光统计方法：采用IPP软件直接测阳性吸光度。
在正常生理状态下，血管平滑肌细胞处于静止状态，主要表现为收缩型；血管损伤后，血管平滑肌细胞由中膜向内膜迁移，平滑肌细胞的增殖凋亡失平衡，表型由收缩型向合成型转变，血管壁不适重塑，从而引起内膜增生。免疫荧光观察SMA、SM22α在WT和RECS1-KO小鼠血管损伤后的表达变化，结果见图3。SMA、SM22α在血管组织中有表达，RECS1-KO小鼠在术后28天SMA、SM22α的荧光强度均要高于同组的WT小鼠，表明RECS1基因敲除可以促进SMA、SM22α的表达，可抑制平滑肌细胞由收缩型向合成型的表型转换，从而抑制内膜增生。
以上述实施例结果显示，野生型小鼠和RECS1-KO小鼠在血管损伤模型（VI）的诱导下均发生血管损伤后再狭窄。与野生型小鼠相比，RECS1-KO小鼠内膜新生、细胞增殖以及平滑肌细胞表型转换均受到抑制。这些结果表明，RECS1基因敲除可以改善血管损伤诱导的平滑肌细胞的增殖、表型转化和血管新生内膜形成。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (6)
1.RECS1作为药物靶标在筛选预防、缓解和/或治疗血管损伤后再狭窄的药物中的应用。
2.RECS1的抑制剂在制备预防、缓解和/或治疗血管损伤后再狭窄的药物中的应用。
3.一种预防、缓解和/或治疗血管损伤后再狭窄的药物，其特征在于：包含RECS1的抑制剂。
4.一种预防、缓解和/或治疗血管损伤后再狭窄的动脉支架，其特征在于：包被有RECS1的抑制剂。
5.根据权利要求1或2所述的应用或权利要求3所述的药物或权利要求4所述的动脉支架，其特征在于：所述的血管损伤为动脉粥样硬化、动脉粥样硬化介入治疗、移植后动脉病或肺动脉高压引起的血管损伤。
6.根据权利要求2所述的应用或权利要求3所述的药物或权利要求4所述的动脉支架，其特征在于：所述的RECS1的抑制剂为RECS1基因的siRNA、RECS1基因的RNA干扰载体或RECS1的抗体及其他能够抑制RECS1表达的抑制剂中的一种。
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| CN106755265A (zh) * | 2016-12-12 | 2017-05-31 | 武汉大学 | 血液剪切力应答蛋白1在脑卒中疾病中的应用 |
| CN109815870A (zh) * | 2019-01-17 | 2019-05-28 | 华中科技大学 | 细胞表型图像定量分析的高通量功能基因筛选方法及系统 |
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| CN109815870A (zh) * | 2019-01-17 | 2019-05-28 | 华中科技大学 | 细胞表型图像定量分析的高通量功能基因筛选方法及系统 |
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