CN107811997A - 蛋白酶体抑制剂白藜芦醇在预防和治疗心血管疾病中的应用 - Google Patents
蛋白酶体抑制剂白藜芦醇在预防和治疗心血管疾病中的应用 Download PDFInfo
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Abstract
本发明的技术方案在于提出白藜芦醇能够抑制蛋白酶体并预防和治疗心肌病和心力衰竭等心血管疾病的相关应用，特别是白藜芦醇作为蛋白酶体抑制剂防治心肌病和心力衰竭的应用。本发明所述的白藜芦醇的具体应用，解决了传统上没有针对心肌病和心力衰竭等心血管疾病进行有效预防和治疗以及临床药物治疗存在不良反应的问题，为防治心肌病和心力衰竭等心血管疾病提出了新的思路和具体应用。
Description
技术领域
本发明涉及白藜芦醇的新用途，尤其涉及蛋白酶体抑制剂白藜芦醇在预防和治疗心血管疾病中的应用。
背景技术
心肌肥厚是心肌组织为适应心脏血流动力超负荷而产生的代偿性反应。在细胞水平上，心肌肥厚主要表现为细胞体积和重量的增加；在器官水平则表现为心室重量增加及心室壁增厚。病理性心肌肥厚是导致多种心血管疾病(心力衰竭、动脉粥样硬化、心肌梗死及高血压等)发病率和病死率不断升高的独立危险因素之一。在致肥厚因素的刺激下，心肌细胞体积增大，心肌重量增加，同时伴有心肌细胞凋亡和坏死、心脏成纤维细胞增殖和转化以及心肌间质纤维化等病理改变。因此，心脏中多种细胞共同构成了心肌肥厚复杂的病理学基础。
心肌肥厚的本质是蛋白质分解与合成代谢的动态平衡被打破，导致心肌细胞内蛋白质含量增加，泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)在其中发挥重要作用。UPS是真核细胞中蛋白质降解的重要途径，主要包括泛素、泛素激活酶、泛素结合酶、泛素连接酶、去泛素化酶及26S蛋白酶体。泛素是由76个氨基酸组成的高度保守的多肽链。蛋白酶体包括组成型和免疫型，组成型蛋白酶体由20S核心颗粒和19S调节颗粒组成。20S核心颗粒由α-和β-亚基组成的四个环层叠构成，β环内的三种催化亚基β1、β2及β5分别具有半胱氨酸蛋白酶、胰蛋白酶及糜蛋白酶活性。催化β亚基在炎症因子的作用下，被包括β1i、β2i及β5i在内的诱导型β亚基取代并形成免疫蛋白酶体。研究证实，免疫蛋白酶体在心血管疾病中有非常重要的病理生理学意义，可调节包括心肌肥厚等重要疾病的发生发展。
动物实验表明，蛋白酶体抑制剂通过抑制蛋白酶体活性，减少心肌细胞肥大信号通路负性调节蛋白的降解，从而改善心肌肥厚。目前针对蛋白酶体的临床干预尚处于初期，常用药物有硼替佐米、乳孢素以及环氧甲酮等。然而，目前尚无针对心肌病和心力衰竭等心血管疾病的蛋白酶体抑制剂。另外，上述药物存在的不良反应(如血小板减少、周围神经病、中性粒细胞减少症等)一定程度上限制了这些药物的临床应用。因此需要鉴定或开发出一种能够预防和防治心血管疾病的蛋白酶体抑制剂。
白藜芦醇是一种天然的非黄酮类多酚化合物，广泛存在于葡萄、桑葚及花生等植物中。大量动物和人群研究证实，白藜芦醇通过抗氧化、抗炎、调节脂质代谢以及抗血小板聚集等发挥其心血管保护作用。
发明内容
本发明要解决的技术问题是克服现有技术的缺陷，提供白藜芦醇的新用途，即在制药中的新应用。
为了解决上述技术问题，本发明提供了如下的技术方案：
本发明的技术方案在于提出白藜芦醇能够抑制蛋白酶体并预防和治疗心肌病和心力衰竭等心血管疾病的相关应用，特别是白藜芦醇作为蛋白酶体抑制剂防治心肌病和心力衰竭的应用。
白藜芦醇通过抗氧化、抗炎、调节脂质代谢以及抗血小板聚集发挥其心血管保护作用。
本发明所达到的有益效果是：
本发明所述的白藜芦醇的具体应用，解决了传统上没有针对心肌肥厚(多种心血管疾病共有的病理生理进程)等心血管疾病进行有效预防和治疗以及临床药物治疗存在不良反应的问题，为防治心肌病和心力衰竭等心血管疾病提出了新的思路和具体应用。它以主动脉弓缩窄术(transverse aortic constriction,TAC)诱导心肌肥厚的小鼠作为实验对象，以心脏蛋白酶体活性、免疫蛋白酶体亚基蛋白表达水平、心脏超声、心脏重量和大小、心脏横截面苏木素-伊红(hematoxylin-eosin,H-E)、麦胚凝集素(Wheat GermAgglutinin,WGA)、Masson Trichrome以及二氢乙锭(Dihydroethidium,DHE)染色为检测指标。结果显示，白藜芦醇作为一种天然的蛋白酶体抑制剂，对压力超负荷诱导的小鼠心肌肥厚有显著的预防和治疗作用，它将在心肌病和心力衰竭等心血管疾病的防治中发挥重要作用。
附图说明
附图用来提供对本发明的进一步理解，并且构成说明书的一部分，与本发明的实施例一起用于解释本发明，并不构成对本发明的限制。在附图中：
图1白藜芦醇对小鼠心脏蛋白酶体活性的影响。
图2白藜芦醇对小鼠心脏免疫蛋白酶体亚基蛋白表达水平的影响。
图3白藜芦醇对小鼠心功能的影响。
图4白藜芦醇对小鼠心脏重量的影响。
图5心脏横截面的H-E染色。
图6心脏横截面的WGA染色。
图7心脏横截面的Masson Trichrome染色。
图8心脏横截面的DHE染色。
具体实施方式
以下结合附图对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明。
为了更好地理解本发明的实质，下面将用小鼠作为试验来说明其在制药领域的新用途。
建立TAC诱导小鼠心肌肥厚模型：取6-8周龄SPF级雄性C57BL/6小鼠，麻醉后消毒手术区域，剪开颈部至胸骨第二肋间的皮肤，分离肌肉并暴露气管和胸骨，将胸骨柄至连接第二肋间的胸骨从中间剪断。用胸部牵开器将胸腔撑开，将胸腺和脂肪组织与主动脉分离；于无名动脉及左侧颈动脉间穿入6号线，并打2个松结；将27号钝头针头平行于横主动脉置于松结内，将第1个松结迅速系紧，再系紧第2个松结，随后将27号钝头针头取出，缩窄术即完成；移除胸部牵开器及气管插管，逐层缝合胸腔及皮肤。手术1周后行多普勒血流检测左右颈动脉血流比值，以明确主动脉缩窄成功，并于术后1周和2周应用Vevo 2100高分辨率小动物超声影像系统检测心室壁厚度及心功能。
实验分组：36只小鼠随机分为3组(每组12只)：假手术组、TAC组、TAC+白藜芦醇组。假手术组不做结扎后缝合皮肤。TAC+白藜芦醇组于手术前1周至术后2周每日给予白藜芦醇50mg/kg体重灌胃，假手术组及TAC组给予等量溶剂(10％羧甲基纤维素钠溶液)。
建立TAC诱导小鼠心肌肥厚模型的检测平台：
一般情况观察：发育情况、行动、皮毛、饮食、体重等。
记录小鼠存活率。
小鼠心脏蛋白酶体活性和免疫蛋白酶体亚基蛋白表达：行TAC术后2周，荧光多肽底物法检测心脏26S蛋白酶体半胱氨酸蛋白酶、胰蛋白酶及糜蛋白酶样活性，Western blot法检测免疫蛋白酶体β1i、β2i以及β5i亚基的蛋白表达水平。
小鼠心功能检测：采用高分辨率小动物超声影像系统检测小鼠左心室前壁、后壁及室间隔厚度、左心室收缩及舒张末期容积，并计算左心室缩短分数(left ventricularfractional shortening,LVFS)和射血分数(left ventricular ejection fractions,LVEF)。
小鼠心脏大小和重量测定：心功能超声评价完成后，以1％戊巴比妥钠(80mg/kg)麻醉小鼠，用肝素钠0.9％氯化钠液灌洗心脏。摘取心脏，去除多余的0.9％氯化钠液，将小鼠心脏放于翻拍板上用照相机拍大体心脏。随后称质量，计算心脏重量与小鼠体重比值(heart weight/body weight,HW/BW)和心脏重量与胫骨长度比值(heart weight/tibiallength,HW/TL)。
小鼠心肌组织病理形态学检测：心脏称重后于心脏中部垂直于心脏长轴横切，石蜡包埋。自心底向心尖以5μm厚度切片。石蜡切片脱蜡至水，按照试剂盒说明，进行H-E、WGA、Masson Trichrome以及DHE染色，以分别检测心脏的组织结构和炎症反应、心肌细胞轮廓、心肌纤维化以及心脏氧化应激程度。
结果
TAC诱导小鼠心衰模型的建立：假手术组小鼠生长发育良好，皮毛光滑、活动灵活、摄水摄食正常。TAC组术后1周小鼠活动量降低，摄食减少。TAC+白藜芦醇组小鼠状态较TAC组有所好转。假手术组无小鼠死亡，TAC组小鼠存活率为91.7％(11/12)。第2周超声心动图结果显示，与假手术组相比，TAC组小鼠LVFS和LVEF显著升高，提示小鼠心功能代偿性增强，发生心肌肥厚，表明模型建立成功(图3)。
白藜芦醇干预对TAC诱导心肌肥厚的影响：
小鼠心脏蛋白酶体活性和免疫蛋白酶体亚基蛋白表达：采用荧光多肽底物法检测发现，TAC术后2周26S蛋白酶体半胱氨酸蛋白酶、胰蛋白酶及糜蛋白酶样活性明显升高，白藜芦醇干预后均显著降低(图1)；Western blot显示白藜芦醇可明显下调TAC诱导的小鼠心脏免疫蛋白酶体β1i、β2i以及β5i亚基蛋白表达水平(图2)。
小鼠心功能检测：第2周超声心动图结果显示，与TAC组相比，TAC+白藜芦醇组小鼠LVEF和LVFS均明显降低(图3)。说明白藜芦醇能显著改善TAC诱导心肌肥厚的小鼠心功能。
小鼠心脏大小和重量测定：术后第2周收取小鼠心脏，肉眼可见TAC组小鼠心脏体积显著增大(图4)。与假手术组相比，TAC组小鼠HW/BW和HW/TL值显著增加。TAC+白藜芦醇组HW/BW和HW/TL值较TAC组明显降低(图4)。提示白藜芦醇干预能显著减轻TAC导致的小鼠心重增加。
小鼠心肌组织病理形态学检测：与假手术组相比，TAC组小鼠心室壁明显增厚，心室腔明显增大(图5A)，心脏中炎症细胞聚集显著增加(图5B)；心肌细胞明显增大(图6)；心肌间质和血管周围的纤维化面积均显著增加(图7)；心肌氧化应激明显增加(图8)。而上述指标在白藜芦醇干预后均得到明显改善(图5，图6，图7，图8)。
综上所述，白藜芦醇作为一种天然的蛋白酶体抑制剂，对TAC诱导的心肌肥厚有预防和治疗作用。蛋白酶体抑制剂白藜芦醇可作为防治心肌病和心力衰竭等心血管疾病的一种新方法。
最后应说明的是：以上所述仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (2)
1.蛋白酶体抑制剂白藜芦醇在预防和治疗心血管疾病中的应用。
2.根据权利要求1所述的应用，其特征在于，所述的心血管疾病为心肌病和心力衰竭。
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