CN108379552A - 提高cab39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用 - Google Patents
提高cab39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用 Download PDFInfo
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Abstract
本发明涉及生物技术领域，具体是提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用。本发明首次揭示了提高CAB39蛋白表达量的试剂可特异性地抑制主动脉瓣钙化，并且首次揭示了CAB39的表达与主动脉瓣钙化密切相关，从而为心脏瓣膜疾病的防治提供了新的靶点。
Description
技术领域
本发明涉及生物技术领域，具体地说，是提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用。
背景技术
心脏瓣膜疾病包括主动脉瓣病变、二尖瓣病变及三尖瓣病变，心脏瓣膜病是目前危害人类健康的主要疾病之一。其中钙化性主动脉瓣疾病(calcific aortic valvedisease，CAVD)的发病率位居心血管疾病中的第三位，表现为主动脉瓣的纤维化、钙化以及瓣叶交界处的融合，从而造成瓣口面积的狭窄。目前只能通过经体外循环人工主动脉瓣置换术或介入主动脉瓣植入的方式进行治疗。基础研究的进展提示，主动脉瓣钙化是一个细胞萎缩凋亡导致钙盐被动沉积的过程。瓣膜间质细胞是维持主动脉瓣正常形态和生理功能的主要执行者。既往认为，瓣膜钙化是一个“被动的”、“退行性变的”瓣膜疾病过程。近年来众多学者研究表明，CAVD早期，瓣膜病变部位即有纤维蛋白、脂质成分以及钙盐的沉积，并伴随巨噬细胞、T细胞等慢性炎症细胞浸润，提示CAVD是由多因素共同参与、积极调控的疾病过程。钙化瓣膜中骨组织的发现以及成骨细胞表型的存在，提示瓣膜钙化可能是积极调控的异位成骨过程，而瓣膜间质细胞的钙化是疾病发生的重要基础之一。其体外钙化模型作为一种有效工具被广泛应用于钙化性主动脉瓣疾病的机制和药物研究中。
不论其病因学为何，主动脉瓣狭窄导致了左心室收缩压的升高。心室腔内收缩性高血压被心壁的向心型肥大补偿，允许壁应力保持正常。低顺应性的、增厚的左心室变得更加依赖于心房对舒张期充盈的贡献，以致当心房收缩消失时，左心室的工作情况恶化。在舒张期期间，增厚左心室异常的舒张和增加的硬度也导致舒张功能障碍以及左心室和左心房舒张压的升高。心肌衰竭最终由慢性严重性心脏瓣膜堵塞以及收缩状态的减少发展而来。心肌耗氧量因左心室收缩压的升高以及左心室质量的增加而保持在高水平。此外，增加的左心室舒张压减少了心肌灌注所需要的压力梯度。因此，严重的主动脉瓣狭窄产生了其中减少的氧气供应不足以满足高心肌需氧量的疾患，其导致心内膜下缺血。最终，在心肌变力状态减少下，射血分数降至正常范围以下有或没有相关的左心室扩张。左心室舒张末期压的进一步升高继发于伴随或未伴随收缩功能障碍的舒张功能障碍导致了肺静脉高血压。在有灌注缺损的心内膜下心肌的主动脉瓣狭窄中，增加的心肌需氧量可以引起心纹痛、心律不齐以及甚至是猝死。
在严重的主动脉瓣狭窄的情况中，任何主要症状的发展表示重大的生命危险也表示需要进行手术治疗。症状出现后平均生命期望值为一年。目前，开胸或介入下人工主动脉瓣膜置换术是对于症状性主动脉瓣狭窄的唯一治疗方式。对于单独的开胸行主动脉瓣膜置换，十年存活率是相当不错的，甚至是对老年患者。然而，这种技术要求患者足够健康以经受胸骨切开术开胸和开胸手术。手术死亡率特别是老年人中比较高。常需要置换新的瓣且因此二次开胸手术，所以生物修复心脏瓣的有效生命期望的限制对患者和医疗系统的经济损耗都是严重的医学问题。此外，所有修复心脏瓣都有稍微狭窄。继发于血检形成或钙化的修复功能障碍可以导致增加堵塞或引起反流。反流也可以由瓣周漏引起，这个漏位于所述瓣的缝合环区域。与瓣功能障碍相关的波动可以引起溶血和贫血。甚至是正常功能的修复瓣也会在一些患者中引起溶血。在使用修复心脏瓣的患者中，心内膜炎是另一个潜在且主要的并发症。在牙、胃肠和泌尿生殖外科手术以及菌血症相关的其他操作法之前必须施用杭生素预防。此外，一些患者的主动脉尺寸不是足够的大以轻易容纳传统的置换瓣。因此对于相当数量的患者，瓣膜置换是不可能的、不切实际的。
经导管主动脉瓣植入术(TAVI)是近几年新兴的已经成为不能行外科开胸换瓣和外科手术风险高的主动脉瓣重度狭窄患者的一种新的治疗选择，较传统的开放式心脏手术，其早期死亡率较低。然而不同于传统瓣膜置换手术，TAVI技术更强调多学科协作，术前评估需要运用多模态影像学技术，包括超声、CT及MRI等。同时TAVI手术也具有其独特的并发症，包括：冠脉开口堵塞、脑卒中、瓣周漏、传导阻滞、置入瓣膜移位或栓塞等。严重钙化瓣膜由于球囊扩张及瓣膜释放过程中产生钙化碎片，可导致TAVI手术出现较高的卒中发生率，而且TAVI手术经济费用较高。
因此，需要一种针对主动脉瓣狭窄和其他心瓣膜病的非手术疗法。
发明内容
本发明显著不同于现有技术和当前趋势的是，通过提供一种提高CAB39蛋白表达量的方法不但可以预防主动脉瓣狭窄的发展，而且减轻瓣膜钙化程度。本发明的目的在于CAB39的新的医药用途，具体是提供提高CAB39蛋白表达量的试剂在防治心脏瓣膜疾病中的作用及应用。
钙结合蛋白39(Calcium binding protein,CAB39)是一种钙结合蛋白，具体序列见GENBANK(NM_016289、NM_001130849和NM_001130850)。目前关于CAB39功能的研究主要集中在肿瘤领域。CAB39能与LKB1及STRAD形成复合物，影响下游分子腺苷酸活化蛋白激酶(AMPK)活性，调节肿瘤细胞的增殖和侵袭能力，从而参与肝癌(Jiang L,Yan Q,Fang S,LiuM,Li Y,Yuan YF,et al.Calcium-binding protein 39promotes hepatocellularcarcinoma growth and metastasis by activating extracellular signal-regulatedkinase signaling pathway.Hepatology.2017；66(5):1529-1545)、胶质瘤(Godlewski J,Nowicki MO,Bronisz A,Nuovo G,Palatini J,De Lay M,et al.MicroRNA-451regulatesLKB1/AMPK signaling and allows adaptation to metabolic stress in gliomacells.Mol Cell.2010；37(5):620-32)、结直肠癌(Chen MB,Wei MX,Han JY,Wu XY,Li C,Wang J,et al.MicroRNA-451regulates AMPK/mTORC1signaling and fascin1expressionin HT-29colorectal cancer.Cell Signal.2014Jan；26(1):102-9)等肿瘤的发生发展。此外，CAB39可作为Ca2+的缓冲蛋白参与调节细胞内外Ca2+浓度，还可作为转运酶，改变细胞膜上钙通道蛋白的活性，选择性增加细胞膜对Ca2+的摄取(Boudeau J,Baas AF,Deak M,Morrice NA,Kieloch A,Schutkowski M,et al.MO25alpha/beta interact withSTRADalpha/beta enhancing their ability to bind,activate and localize LKB1inthe cytoplasm.EMBO J.2003；22(19):5102-14.)。
为了实现上述目的，本发明的第一方面，提供提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用。
进一步的，所述的提高CAB39蛋白表达量的试剂包括以下任一：
A)CAB39蛋白；
B)含有CAB39蛋白编码基因的重组载体；
C)含有CAB39蛋白编码基因的重组病毒；
D)CAB39类似物。
上述C)中，可以是含有CAB39蛋白编码基因的重组慢病毒、含有CAB39蛋白编码基因的重组腺病毒、含有CAB39蛋白编码基因的重组腺相关病毒等。
上述D)中，可以是重组CAB39多肽。
进一步的，所述的心脏瓣膜疾病为钙化性主动脉瓣疾病(calcific aortic valvedisease，CAVD)。
进一步的，所述的提高CAB39蛋白表达量的试剂通过有效延缓瓣膜钙化，并通过激活AMPK/mTOR信号通路来发挥抑制瓣膜间质细胞钙化的作用。
进一步的，所述的预防或治疗心脏瓣膜疾病药物是由提高CAB39蛋白表达量的试剂作为活性成分，与常规药用载体制成的药物组合物。
进一步的，所述的药物组合物是片剂、分散片、含片、口崩片、缓释片、胶囊剂、软胶囊剂、滴丸、颗粒剂、注射剂、粉针剂或气雾剂。
本发明的第二方面，提供一种预防或治疗心脏瓣膜疾病的药物组合物，其活性成分为提高CAB39蛋白表达量的试剂。
进一步的，所述的预防或治疗心脏瓣膜疾病的药物组合物还包括药学上可接受的载体或辅料。
本发明的第三方面，提供CAB39在筛选预防或治疗心脏瓣膜疾病药物中的应用，所述的预防或治疗心脏瓣膜疾病药物为提高主动脉瓣组织中CAB39表达水平的药物。
在另一优选例中，所述的筛选方法包括：对获得的潜在物质进行进一步的细胞实验和/或动物试验，以从候选物质中进一步选择和确定对于预防或治疗心脏瓣膜疾病有用的物质。
本发明的第四方面，提供一种延缓或治疗钙化性主动脉瓣疾病的方法，所述方法包括：上调所述目标体内CAB39的表达水平以延缓主动脉瓣膜钙化的发生，下调CAB39的表达水平将促进主动脉瓣钙化的进程。
本发明中，所述术语一种状态、疾病、失调或病症的“治疗”或“治疗”包括：
(1)预防或延缓受治疗者的状态、疾病、失调或病症的临床症状的出现，所述受治疗者可以是受到状态、疾病、失调或病症的折磨或易受到状态、疾病、失调或病症的感染，但并未经历或者表现出状态、疾病、失调或病症的临床或亚临床症状；
(2)抑制所述状态、疾病、失调或病症，即阻止或减轻状态、疾病、失调或病症或至少其一种临床或亚临床症状的发展；或
(3)缓解所述状态、疾病、失调或病症，即导致所述状态、疾病、失调或病症或至少其一种临床或亚临床症状的消退。
受治疗者从治疗中获得的益处是统计学显著的或者至少是所述受治疗者或医生可以感觉到的。
所述术语“受治疗者”包括哺乳动物(特别是人)和其他动物，如家畜(如，家养宠物包括猫和狗)以及非家畜(如野生动物)。
“治疗有效量”是指一种化合物的量，当施用于受治疗者以治疗状态、疾病、失调或病症时，可足以实现所述治疗。所述“治疗有效量”根据以下因素变化化合物、状态、疾病、失调或病症和其严重性以及接受治疗的受治疗者的年龄、体重、身体状况和响应度。
药物组合物
本发明的药物组合物包括至少一种本发明的化合物和药学上可接受的赋形剂(如药学上可接受的载体或稀释剂)。优选地，所述药物组合物包括治疗有效量的本发明所述的化合物。本发明所述的化合物可与药学上可接受的赋形剂(如载体或稀释剂)结合，或被载体稀释，或被封入载体，该载体可以为胶囊、香囊、纸或其他容器的形式。
合适载体的例子包括且不限于水、盐溶液、醇、聚乙二醇、多羟乙氧基蓖麻油、花生油、橄榄油、明胶、乳糖、白土、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石、明胶、琼脂、果胶、阿拉伯树胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸甘油一酸酯和甘油二酯、季戊四醇脂肪酸酯、聚氧乙烯、羟甲基纤维素和聚乙烯毗咯烷酮。
所述载体或稀释剂可以包括一种持续释放的材料，如单独或与蜡混合的甘油单硬脂酸酯或甘油二硬脂酸酯。
所述药物组合物也可以包括一种或多种药学上可接受的助剂、润湿剂、乳化剂、悬浮剂、防腐剂、影响渗透压的盐、缓冲剂、甜味剂、调味剂、着色剂、或前述的任何组合。本发明所述药物组合物可以通过使用本领域所熟知的步骤配制，以对受治疗者提供施用后活性成分的快速、持续、或延缓释放。
本发明所述药物组合物可以通过常规技术制备。例如，所述活性化合物可以同载体混合，或被载体稀释，或被封入载体，其可以为安饥、胶囊、香囊、纸或其他容器的形式。当载体作为稀释剂时，它可以是固体、半固体、或者液体材料，其作为所述活性化合物的运载体、赋形剂或介质。所述活性化合物可以被吸附在颗粒状固体容器如在香囊中上。所述药物组合物可以为常规形式，例如，胶囊、片剂、气溶胶、溶液、悬浮液或用于局部应用的产品。
施用途径可以是任何将本发明的活性化合物有效地运送到合适或期望的作用部位的途径。合适的施用途径包括且不限于口服、鼻、肺、含服、皮下、皮内、经皮、胃肠外、直肠、贮库，皮下、静脉内、尿道内、肌肉内、鼻内、眼(如用眼用溶液)或局部(如用局部软膏)。
本发明优点在于：
本发明首次揭示了提高CAB39蛋白表达量的试剂可特异性地抑制主动脉瓣钙化，并且首次揭示了CAB39的表达与主动脉瓣钙化密切相关，从而为心脏瓣膜疾病的防治提供了新的靶点。
附图说明
图1.钙化主动脉瓣中CAB39的定量及定位分析。
A，定量PCR显示与对照组相比，CAB39在钙化的主动脉瓣膜中表达显著降低，**P<0.01。B，Western blot检测瓣膜组织中CAB39的表达，结果显示CAB39在正常瓣膜中高表达，而在钙化瓣膜中表达明显降低。C，免疫组织化学染色显示CAB39在正常瓣膜中高表达，在钙化瓣膜中的表达显著降低，且主要表达在瓣膜间质细胞中。
图2.过表达CAB39延缓瓣膜钙化进程。
A，茜素红染色显示与对照组相比，过表达CAB39后瓣膜间质细胞钙盐结节明显减少。B，钙浓度分析显示过表达CAB39后，瓣膜间质细胞间钙盐沉积明显减少，*P<0.05。C，碱性磷酸酶活性检测发现与对照组相比，过表达CAB39瓣膜间质细胞的碱性磷酸酶活性降低，**P<0.01。
图3.敲低CAB39促进瓣膜钙化进程。
A，茜素红染色显示与对照组相比，敲低CAB39后瓣膜间质细胞钙盐结节明显增加。B，钙浓度分析显示敲低CAB39后，瓣膜间质细胞间钙盐沉积明显增加，**P<0.01。C，碱性磷酸酶活性检测发现与对照组相比，敲低CAB39瓣膜间质细胞的碱性磷酸酶活性显著增加，**P<0.01。
图4.CAB39通过激活AMPK/mTOR信号通路发挥抑制瓣膜钙化的作用。
A，Western blot检测过表达CAB39后，CAB39相关复合物LKB1和STRAD的表达变化，结果显示过表达CAB39后，LKB1的表达明显升高，STRAD的表达增加，但增加没有统计学差异。B，Western blot检测过表达CAB39后AMPK及磷酸化的AMPK(p-AMPK)和mTOR及磷酸化的mTOR(p-mTOR)的表达变化，结果显示AMPK与mTOR的表达未见明显变化，p-AMPK的表达明显升高，p-mTOR的表达明显降低。
具体实施方式
以下将结合具体实施例进一步阐述本发明。这些实施例仅用于阐述本发明，而不用于限制本发明的范围。下述实施例中未注明具体实验条件的实验方法，通常按照常规条件，分子克隆(Molecular Cloning:A Laboratory Manual，3rd ed.)中所述的条件，或按照制造厂商所建议的条件。
材料和方法
组织标本收集及处理
经医院伦理委员会批准及患者知情同意，钙化主动脉瓣取自行人工主动脉瓣置换术的CAVD患者，正常主动脉瓣取自心脏移植患者为正常对照组。将组织标本迅速固定于福尔马林或冻存于液氮中以待检测。
人瓣膜间质细胞的分离及培养
将手术获得的正常主动脉瓣膜组织置于Ⅰ型胶原酶中37℃消化10分钟，使用灭菌棉签将表面的而瓣膜内皮细胞擦除，再置于Ⅱ型胶原酶中37℃震荡消化2小时，过滤、离心后重悬。加入含链霉素、青霉素双抗、10％胎牛血清的DMEM培养基，置于含5％CO2的37℃恒温培养箱中进行培养，实验使用3-6代细胞，每2-4天换液。
体外钙化模型及钙沉积检测
使用配方为2mmol/L磷酸二氢钠、50μg/mL抗坏血酸、10-7mol/L胰岛素的钙化培养基诱导瓣膜间质细胞7天构建体外钙化模型。使用钙测定试剂盒(QuantiChrom CalciumAssay Kit,BioAssay Systems)通过比色定量的方法测定的培养细胞中的钙浓度。
茜素红染色
配制pH＝4.3的1％茜素红S染色液对钙结节进行染色，在一般光学显微镜下观察细胞钙化程度，钙沉积阳性细胞呈现桔红色。
实时荧光定量PCR
人瓣膜组织以及培养细胞的总RNA用TRIzol(Invitrogen)抽提。紫外分光光度计测定RNA浓度和纯度。取500ng总RNA逆转录为cDNA，PCR法进行目的基因扩增，各反应体系均以GAPDH作为内参引物，并通过溶解曲线和琼脂糖凝胶电泳确定基因扩增的特异性。
免疫组织化学染色
取钙化组瓣膜与对照组瓣膜，用4％多聚甲醛固定过夜，石蜡包埋。石蜡切片(4μm)后用S-P法进行免疫组织化学染色，使用碧云天免疫染色一抗稀释液以特定比例稀释Anti-CAB39(1:3000,abcam)，置于湿盒中4℃过夜，洗脱后常温孵育相应酶标二抗30分钟，利用DAB显色，以出现棕黄色为阳性染色，苏木素复染后脱水封片，正置显微镜下观察分析，使用Image Pro Plus软件进行图像分析。
统计学分析
用SPSS 19.0软件进行数据处理分析，所有计量资料数据采用平均值±标准误进行表示，组间比较使用t检验，以P<0.05为差异有统计学意义。
实施例1：CAB39组织表达谱分析
本实施例收集CAVD患者的钙化主动脉瓣组织作为实验组，心脏移植患者的正常主动脉瓣组织作为对照组。利用实时荧光定量PCR的方法检测两组瓣膜组织中CAB39的mRNA水平的表达变化，结果显示CAB39在钙化的主动脉瓣膜中表达显著降低，**P<0.01(图1A)。通过western blot的方法检测瓣膜组织中CAB39蛋白水平的表达变化，结果显示CAB39在正常瓣膜中高表达，而在钙化瓣膜中表达明显降低(图1B)。
实施例2：正常瓣膜组织中高丰度的CAB39主要表达于瓣膜间质细胞
本实施例采用免疫组织化学染色的方法检测瓣膜组织中CAB39的表达定位，结果发现CAB39在正常瓣膜中高表达，在钙化瓣膜中的表达显著降低，且主要表达在瓣膜间质细胞中(图1C)。
实施例3：过表达CAB39可延缓瓣膜钙化进程
本实施例分离培养了瓣膜间质细胞，构建了CAB39过表达腺病毒。利用CAB39过表达腺病毒转染瓣膜间质细胞48小时后，利用钙化培养基诱导瓣膜间质细胞7天构建体外钙化模型。利用茜素红染色、钙浓度分析、碱性磷酸酶活性检测评定瓣膜钙化程度。茜素红染色显示与对照组相比，过表达CAB39后瓣膜间质细胞钙盐结节明显减少(图2A)。钙浓度分析显示过表达CAB39后，瓣膜间质细胞间钙盐沉积明显减少，*P<0.05(图2B)。碱性磷酸酶活性检测发现与对照组相比，过表达CAB39瓣膜间质细胞的碱性磷酸酶活性降低，**P<0.01(图2C)。
实施例4：敲低CAB39可促进瓣膜钙化进程
前一部分实验结果表明，CAB39过表达能够显著抑制瓣膜间质细胞钙化。为更好的探讨CAB39的内源性功能，本工作通过瓣膜间质细胞转染CAB39敲低腺病毒，进而沉默内源性的CAB39。转染48小时后利用钙化培养基诱导瓣膜间质细胞7天构建体外钙化模型。利用茜素红染色、钙浓度分析、碱性磷酸酶活性检测评定瓣膜钙化程度。结果发现茜素红染色显示与对照组相比，敲低CAB39后瓣膜间质细胞钙盐结节明显增加(图3A)。钙浓度分析显示敲低CAB39后，瓣膜间质细胞间钙盐沉积明显增加，**P<0.01(图3B)。碱性磷酸酶活性检测发现与对照组相比，敲低CAB39瓣膜间质细胞的碱性磷酸酶活性显著增加，**P<0.01(图3C)。
实施例5：CAB39通过激活AMPK/mTOR信号通路发挥抑制瓣膜钙化的作用
上述实验证明了CAB39在瓣膜间质细胞钙化中的作用，而CAB39是一种钙离子结合蛋白，它是LKB1复合体的组成部分，在该复合体中起到重要的介导作用。本发明随后利用western blot对其复合体的结合物LKB1与STRAD进行检测，结果发现过表达CAB39后，LKB1的表达明显升高，STRAD的表达增加，但增加没有统计学差异(图4A)。当CAB39与复合体中其他两个成分LKB1与STRAD紧密结合时，LKB1复合体便能够激活下游分子AMPK，因此本发明人通过western blot检测CAB39复合体下游AMPK和mTOR的蛋白表达水平，并检测磷酸化的AMPK(p-AMPK)和mTOR及磷酸化的mTOR(p-mTOR)的表达变化来检测两条信号通路的活性，结果显示AMPK与mTOR的表达未见明显变化，p-AMPK的表达明显升高，p-mTOR的表达明显降低(图4B)。
以上结果证实，CAB39能够有效延缓瓣膜钙化，并通过激活AMPK/mTOR信号通路来发挥抑制瓣膜间质细胞钙化的作用。
讨论
组织病理学、实验和临床数据表明钙化主动脉瓣狭窄是一个主动性疾病过程并伴随着脂蛋白沉积、炎症和由细胞通路介导的主动性瓣叶钙化。
CAB39是一种钙离子结合蛋白，它是LKB1复合体的组成部分，在该复合体中起到重要的介导作用。当CAB39与复合体中其他两个成分LKB1与STRAD紧密结合时，LKB1复合体便能够激活下游分子。根据目前的研究，LKB1复合体激活后主要激活AMPK分子引起一系列的生物学效应。目前CAB39直接参与瓣膜间质细胞钙化的机制研究尚未有报道，但LBK1复合体下游分子AMPK是成骨分化中的重要分子，其主要对细胞内的能量供应进行调控，在细胞增殖、迁移等方面都有重要的调控作用。目前AMPK在成骨分化中扮演的角色存在争议，一些研究发现在成骨细胞内，AMPK经LKB1活化后会促进骨形成和骨基质矿化，抑制其活化会抑制骨小结的形成(Pantovic A,Krstic A,Janjetovic K,Kocic J,Harhaji-Trajkovic L,Bugarski D et al.Coordinated time-dependent modulation of AMPK/Akt/mTORsignaling and autophagy controls osteogenic differentiation of humanmesenchymal stem cells.Bone.2013；52(1):524-31。Bandow K,Kusuyama J,Kakimoto K,Ohnishi T,Matsuguchi T,AMP-activated protein kinase(AMPK)activity negativelyregulates chondrogenic differentiation.Bone.2015；74:125-33)。但成骨细胞分化过程中AMPK活性会下降，两者之间存在功能上的联系，进一步限制葡萄糖的供给或加入二甲双胍后AMPKα亚基的磷酸化程度会增高，细胞外矿化程度会降低，Runx2和OPN等成骨标志物的表达同时也明显减低(Kim EK,Lim S,Park JM,Seo JK,Kim JH,Kim KT et al.Humanmesenchymal stem cell differentiation to the osteogenic or adipogenic lineageis regulated by AMP-activated protein kinase.J Cell Physiol.2012Apr；227(4):1680-7)。其机制可能与成骨分化需要大量能量有关，AMPK活化后会开启产生ATP的通路并关闭消耗ATP的通路，AMPK活性降低后会保证成骨诱导过程所需的能量供应。
另一方面，mTOR也与成骨分化密切相关，它的激活与AMPK十分相关，AMPK激活后会抑制mTOR的激活，而AMPK失活会激活mTOR。有实验证实AMPK在受到抑制后会激活mTOR的表达，并激活mTOR的下游分子P70S6K，而BMP，特别是BMP7可通过此分子促进成骨诱导，因此mTOR应该对成骨分化起到了促进作用(Yeh LC,Ma X,Ford JJ,Adamo ML,LeeJC.Rapamycin inhibits BMP-7-induced osteogenic and lipogenic markerexpressions in fetal rat calvarial cells.J Cell Biochem.2013Aug；114(8):1760-71.)。
本发明首先确定CAB39在钙化瓣膜中表达量显著降低。在对转染CAB39类似物后成骨诱导7天的人瓣膜间质细胞进行茜素红染色及钙沉积检测时发现过表达CAB39后瓣膜间质细胞钙盐结节及钙沉积明显减少且碱性磷酸酶活性显著降低，而敲低CAB39后结果相反。
结合之前的分析，本发明认为通过CAB39表达水平升高后与复合体中其他两个成分LKB1与STRAD紧密结合并激活了下游AMPK，而AMPK激活后抑制了mTOR，使mTOR介导的促进成骨机制受到抑制，从而抑制了瓣膜间质细胞钙化发挥延缓瓣膜钙化的作用。
虽然本发明描述了具体的例子涉及调节钙化性主动脉瓣疾病，但是本领域技术人员将很容易理解这些实验可以预测对人或其他哺乳动物的生物效果，和或可作为在人或其他哺乳动物中使用本发明来研究其他相似瓣膜疾病的模型。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可做出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (9)
1.提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用。
2.根据权利要求1所述的提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用，其特征在于，所述的提高CAB39蛋白表达量的试剂包括以下任一：
A)CAB39蛋白；
B)含有CAB39蛋白编码基因的重组载体；
C)含有CAB39蛋白编码基因的重组病毒；
D)CAB39类似物。
3.根据权利要求1所述的提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用，其特征在于，所述的C)中，含有CAB39蛋白编码基因的重组病毒选自含有CAB39蛋白编码基因的重组慢病毒、含有CAB39蛋白编码基因的重组腺病毒、含有CAB39蛋白编码基因的重组腺相关病毒。
4.根据权利要求1所述的提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用，其特征在于，所述的D)中，CAB39类似物是重组CAB39多肽。
5.根据权利要求1所述的提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用，其特征在于，所述的心脏瓣膜疾病为钙化性主动脉瓣疾病。
6.根据权利要求1所述的提高CAB39蛋白表达量的试剂在制备预防或治疗心脏瓣膜疾病药物中的应用，其特征在于，所述的提高CAB39蛋白表达量的试剂通过有效延缓瓣膜钙化，并通过激活AMPK/mTOR信号通路来发挥抑制瓣膜间质细胞钙化的作用。
7.一种预防或治疗心脏瓣膜疾病的药物组合物，其活性成分为提高CAB39蛋白表达量的试剂。
8.根据权利要求7所述的预防或治疗心脏瓣膜疾病的药物组合物，其特征在于，所述的预防或治疗心脏瓣膜疾病的药物组合物还包括药学上可接受的载体或辅料。
9.CAB39在筛选预防或治疗心脏瓣膜疾病药物中的应用，所述的预防或治疗心脏瓣膜疾病药物为提高主动脉瓣组织中CAB39表达水平的药物。
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