CN117018200A - Sirt6激活剂在制备治疗和预防血管衰老相关疾病药物中的应用 - Google Patents
Sirt6激活剂在制备治疗和预防血管衰老相关疾病药物中的应用 Download PDFInfo
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Abstract
本发明提供SIRT6激活剂作为活性成分在制备治疗和预防血管衰老相关疾病中的应用。在血管平滑肌细胞中应用SIRT6激活剂可以显著抑制血管平滑肌细胞衰老和衰老相关炎症因子的增加。在CaCl2孵育的方法构建的小鼠胸主动脉瘤模型中，应用SIRT6激活剂可以明显抑制动脉瘤表型。
Description
技术领域
本发明属于医药领域，具体涉及胸主动脉瘤的治疗。
背景技术
胸主动脉瘤(Thoracic Aortic Aneurysm，TAA)是主要累及胸主动脉段的瘤样病变。影响主动脉正常生理功能的主要有三种疾病：动脉粥样硬化，动脉瘤和动脉夹层，后两者是引起主动脉急性动脉综合症的主要元凶。胸主动脉瘤常被称为隐形杀手，因为发病前往往没有任何症状，而一旦瘤体破裂，死亡率非常高。至少有22％的急性动脉综合症(包括动脉瘤或夹层)的人发病后，去医院接受治疗之前就已死亡，入院后除了手术之外，也没有很好的治疗措施。甚至这些数据并不能充分反应胸主动脉瘤的发病率和死亡率，因为胸主动脉瘤发病十分隐匿，对于突然的死亡，并不知晓原因。因此寻找胸主动脉瘤可能的预防/治疗措施显得尤为重要。
以往研究认为，对于家族性TAA多是由特定基因突变等遗传因素导致，如马凡氏综合症，由于fibrillin 1基因的突变导致，Loeys–Dietz syndrome综合症由于TGFbR1/TGFbR2基因突变导致。这部分家族性的胸主动脉瘤大约占了总胸主动脉瘤的21％。对于散发性的胸主动脉瘤，该部分患者发病年龄晚，发病原因和致病机制不明确。家族性胸主动脉瘤的发病年龄约是56.8岁，而散发的胸主动脉瘤患者平均年龄约64.3岁，提示老龄可能是散发性胸主动脉瘤发病的危险因素。随着年龄的增长，胸主动脉瘤的破裂比率也大幅度提高。研究显示，年龄每增大10岁，胸主动脉瘤的破裂比率升高2.6倍。并且这种随着年龄的增长而增高的危险系数和性别基本无关。提示老龄是胸主动脉瘤破裂的独立危险因素之一。
机体通过促进细胞进入细胞周期抑制，即细胞衰老，来清除体内的受损细胞，这种现象不仅出现在肿瘤抑制中，在其他非肿瘤病变中也比较常见。从人类动脉粥样硬化斑块中提取的细胞在体外培养中比正常细胞能更快的进入衰老状态，并且在组织水平也用衰老相关半乳糖苷酶(SA-βGal)染色的方法确定斑块中存在着衰老的内皮细胞和平滑肌细胞，这些细胞主要位于内膜，与病理状态下细胞持续分裂有关。体外培养实验证实衰老的血管平滑肌细胞对NO以及β-肾上腺素受体刺激的反应是降低的，从而促进了老龄个体中血管舒张活性的降低。衰老的平滑肌细胞产生弹性蛋白酶的能力有所增高，这与成纤维细胞相反，衰老的平滑肌细胞更容易凋亡。衰老的平滑肌可以通过分泌炎症相关因子诱导血管的慢性炎症，致使动脉粥样硬化的发生。重组核纤层蛋白前体A可以导致持续的DNA损伤信号激活，促使平滑肌细胞衰老和炎症分泌的增加。提示衰老的平滑肌细胞可能参与了衰老相关血管疾病的发生发展，我们课题组已发表的研究证明，血管平滑肌细胞衰老在胸主动脉瘤发生发展中起重要作用。
SIRT6是NAD+依赖的III类组蛋白去乙酰化酶Sirtuins(SIRT1-7)家族中的一员。SIRT6跟衰老和寿命关系密切。2006年Mostoslavsky等最早报道，SIRT6敲除鼠表现出毛色变灰，脊柱侧弯，骨密度降低，低血糖，恶病质等明显的早老症状。2012年又有研究证明，SIRT6可以激活IGF1信号通路，并且SIRT6转基因鼠和野生型小鼠相比，寿命明显延长。
SIRT6在血管中的作用近几年也逐渐引起大家关注。2016年有研究证明SIRT6可以通过保护内皮细胞的功能，从而抑制小鼠动脉粥样硬化的发生。并且针对Sirt6基因的大范围人群测序显示，SIRT6的遗传突变(rs107251,rs352493,rs3760908)和冠状动脉疾病的严重程度有关。我们课题组2023年7月最新发表的研究证明SIRT6敲除可以引起小鼠血管平滑肌细胞衰老，加重胸主动脉瘤表型，但在发表文章中仅用了血管紧张素AngII诱导的小鼠胸主动脉瘤模型，证明SIRT6敲除可以加重胸主动脉瘤，而胸主动脉瘤却包含多种类型，SIRT6对于其他类型的胸主动脉瘤有无影响暂时未知。并且该文章对于SIRT6的应用问题没有解决。SIRT6激活剂能否抑制胸动脉瘤发生？SIRT6激活剂能否用于治疗其他小鼠模型的胸主动脉瘤？这些问题目前都是未知。
综上所述，SIRT6激活剂能否作为治疗胸主动脉瘤的一种潜在药物呢？
发明内容
为了解决上述问题，本发明提供SIRT6激活剂作为活性成分在制备治疗和预防血管衰老相关疾病中的应用。
其中，所述血管衰老相关疾病为胸主动脉瘤，腹主动脉瘤，其他位置动脉瘤，以及其他衰老相关血管疾病。
优选地，所述血管衰老相关疾病为胸主动脉瘤。更优选地，所述血管衰老相关疾病为非SIRT6表达下调的胸主动脉瘤。
其中，所述药物还可以包括药学或免疫学上可接受的赋形剂、载体和/或稀释剂。
其中，SIRT6激活剂包括但不限于化学合成类化合物如MDL800、MDL811、NAD+前体相关化合物等，淫羊藿苷、槲皮素等天然植物提取物，以及SGLT2抑制剂、GLP-1受体激动剂等已上市临床药物。
其中，所述药物的剂型可为口服剂、栓剂、注射剂或涂敷剂等。
本申请在人血管平滑肌细胞中应用SIRT6激活剂可以显著抑制血管平滑肌细胞衰老和衰老相关炎症因子的增加。在CaCl2孵育的方法构建的小鼠胸主动脉瘤模型中(该模型中SIRT6表达未下调)，应用SIRT6激活剂可以明显抑制动脉瘤表型。
附图说明
图1所示为用血管紧张素AngII诱导人血管平滑肌细胞衰老，在含有或不含有SIRT6激活剂MDL-800的人SMC中的SA-b-gal染色。蓝色表示SA-b-gal阳性细胞。阳性细胞的定量显示在右侧。数据以平均值±SEM表示。
图2所示为用血管紧张素AngIII诱导人血管平滑肌细胞衰老，含有或不含有SIRT6激活剂MDL-800的人血管平滑肌细胞中衰老相关标志物和炎症因子的实时PCR。数据以平均值±SEM表示。
图3所示为用多次传代的方法诱导人血管平滑肌细胞衰老，在含有或不含有SIRT6激活剂MDL-800的人血管平滑肌细胞中的SA-b-gal染色。蓝色表示SA-b-gal阳性细胞。阳性细胞的定量显示在右侧。数据以平均值±SEM表示。P10表示传至第10代。
图4CaCl2小鼠胸主动脉瘤模型和对照中Sirt6表达。
图5所示为用SIRT6激活剂MDL-800孵育CaCl2诱导的小鼠胸主动脉瘤模型。
图6所示为SIRT6激活剂NR孵育CaCl2诱导的小鼠胸主动脉瘤模型。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
本研究得到北京协和医院医学伦理委员会(PUMCH)的批准，并符合伦理准则，所有参与者都签署了知情同意书。
实施例没有明确说明的试验方法，均是本领域常规的试验方法。
实施例1SIRT6激活剂可以抑制血管平滑肌细胞衰老
小鼠体内实验证明，SIRT6在平滑肌中特异性敲除后，能明显导致血管中膜平滑肌细胞的衰老和血管平滑肌细胞炎症因子的分泌增加。那应用SIRT6激活剂能否抑制平滑肌衰老从而抑制血管平滑肌衰老呢？我们选用SIRT6特异性激活剂MDL-800进行了体外实验。
我们在人原代血管平滑肌细胞中，用血管紧张素II诱导细胞衰老，同时用SIRT6特异性激活剂MDL-800(20uM，DMSO溶解)孵育，MDL-800是属于化学合成类化合物，它可以结合SIRT6的表面变构位点，以促进SIRT6脱乙酰酶和去肉豆蔻酰酶活性。SA-βGal染色发现SIRT6激活剂能明显抑制人血管平滑肌细胞的衰老(图1)。同时荧光定量PCR显示，SIRT6激活剂能明显抑制衰老相关标志物p53,p21的上升，并且抑制衰老相关炎症因子的表达(图2)。
除了血管紧张素II诱导衰老，我们同步用了多次传代诱导血管平滑肌细胞衰老方法。我们把人血管平滑肌细胞进行多次传代诱导衰老(8～9代以上)，多次传代时分两组，一组同时做加SIRT6特异性激活剂MDL-800(20uM，DMSO溶解)孵育，另一组加DMSO对照。结果表明，SIRT6特异性激活剂MDL-800能明显抑制多次传代诱导的血管平滑肌细胞衰老(图3)。
这些结果表明，SIRT6激活剂可以明显抑制血管平滑肌细胞衰老。
实施例2SIRT6激活剂可以抑制胸主动脉瘤发生和疾病进展
我们利用CaCl2孵育的方法构建胸主动脉瘤模型(浸有0.5mol/L CaCl2溶液的海绵敷贴小鼠升主动脉/主动脉弓15分钟，开胸手术小鼠需用呼吸机辅助通气，4周后观察胸主动脉瘤形成，该模型中SIRT6表达未下调(图4)。CaCl2孵育是直接刺激血管，引起血管钙化弹性纤维破坏，直接导致动脉瘤，这种刺激比较强、直接，体内SIRT6完全来不及反应。
用皮下埋缓释泵方法给予小鼠SIRT6特异性激活剂MDL-800(50mg/kg，用DMSO溶解)和DMSO对照，发现MDL-800治疗能明显抑制胸主动脉瘤形成(图5)。
此外我们应用SIRT6另一种激活剂烟酰胺核糖(Nicotinamide Riboside，NR)，同步实验。NR是维生素B3的衍生物，是烟酰胺腺嘌呤二核苷酸(NAD+)的前体底物，摄入后可以增加NAD+水平，来促进SIRT6去乙酰酶活性。利用CaCl2孵育的方法构建胸主动脉瘤模型(浸有0.5mol/L CaCl2溶液的海绵敷贴小鼠升主动脉/主动脉弓15分钟，开胸手术小鼠需用呼吸机辅助通气，4周后观察胸主动脉瘤形成)，同时用皮下埋缓释泵方法给予小鼠SIRT6激活剂NR(Sigma Aldrich,200mg/kg,生理盐水溶解)和生理盐水对照，发现SIRT6激活剂NR也可以明显抑制小鼠胸主动脉瘤形成(图6)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.SIRT6激活剂作为活性成分在制备治疗和预防血管衰老相关疾病药物中的应用。
2.如权利要求1所述的应用，其特征在于，所述血管衰老相关疾病为胸主动脉瘤。
3.如权利要求1或2所述的应用，其特征在于，所述药物还包括药学或免疫学上可接受的赋形剂、载体和/或稀释剂。
4.如权利要求1或2所述的应用，其特征在于，所述SIRT6激活剂包括但不限于MDL800、MDL811、NAD+前体相关化合物、淫羊藿苷、槲皮素，以及SGLT2抑制剂、GLP-1受体激动剂。
5.如权利要求1或2所述的应用，其特征在于，所述药物剂型包括口服剂、栓剂、注射剂或涂敷剂。
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