CN117665271A - 心肌缺血再灌注损伤标记物、及其代谢促进剂和应用 - Google Patents
心肌缺血再灌注损伤标记物、及其代谢促进剂和应用 Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种心肌缺血再灌注损伤的标记物、及其代谢促进剂和应用,涉及生物医药技术领域。一种心肌缺血再灌注损伤标记物,为氧化态烟酰胺腺嘌呤二核苷酸(NAD+)。本发明还提供了上述心肌缺血再灌注损伤标记物NAD+代谢促进剂,为中药来源的酚酸类成分,包括丹酚酸B、和/或α‑β不饱和酚酸,其中所述的α‑β不饱和酚酸包括阿魏酸、绿原酸、咖啡酸、迷迭香酸、或原儿茶酸。本发明心肌缺血再灌注损伤标记物NAD+是一种能够同时驱动第一信使和第二信使的信号转导,可多途径预防、调节MIRI与心肌梗死的新型标记物分子,对干预MIRI及其心肌梗死的药物研发有重要的指导意义。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及一种心肌缺血再灌注损伤的标记物、及其代谢促进剂和应用。
背景技术
心肌缺血再灌注损伤(myocardial ischemia-reperfusion injury,MIRI),是一种在心脏病和心血管医学领域中,针对患者术后频发的二次损伤。MIRI是由于在手术中经过部分或完全阻塞冠状动脉,导致缺血的心肌发生超微结构、能量代谢、心功能和电生理等一系列损伤变化而引起的,在血流再灌注后会加重这些损伤性变化的程度,甚至会诱发进行性加重的心肌梗死病理过程。对其发生机制的研究,认为主要与心肌组织的氧化应激、钙离子超负荷、白细胞炎性反应及高能磷酸化合物缺乏等有关。
临床上,MIRI发病人群常见于心脏休克治疗、冠状动脉旁路移植、经皮冠状动脉介入治疗、经皮穿刺瓣膜成形、二尖瓣修复、冠状动脉支架搭桥、心脏复苏、外科体外循环、心律失常射频治疗和心脏移植等手术患者中。患者常伴有剧烈、持久的胸骨后疼痛,休息与硝酸酯类药物不能完全缓解,进行性心电图变化,并可诱发心律失常、休克或心力衰竭等病症。病情严重者可形成冠状动脉的持续性血栓、甚至急性的心肌梗死。临床上,心肌梗死患者多采用吸氧和药物溶栓治疗,但过度的溶栓治疗又会导致患者易发生抗凝血异常,冠状动脉大出血、甚至死亡。因此,MIRI诱导的心肌梗死已经成为严重危害我国人民生命安全的“隐形杀手”。
MIRI诊断的临床样本,来源于心肌已严重损伤、且导致急性心肌梗死或者死亡风险较高的患者血液。样本采集受诸多苛刻条件的限制,首先是必须在患者死亡前可取得新鲜血样,其次是血样的生物标志物须有显著改变。现有的MIRI的生物标志物采用心肌肌钙蛋白(CTN-T)变化,其增加幅度设定值:≥99%参考值上限、截点变异度≤10%;另外,还需至少确诊一项心电图或影像学的病理性结果,如伴随心肌缺血、新的ST段抬高、ST-T动态演变、左束支传导阻滞、冠状动脉造影或新鲜血栓形成。对于基线CTN-T正常的动脉导管插入术患者,CTN-T增加值可被动态地调整为:≥3倍正常上限。而对于冠状动脉旁路移植术患者,这个数值超过正常上限5倍。尽管如此,对于其他类型的缺血性心脏手术患者,其体内的CTN-T标记物准确变化则未予以定义。除了CTN-T,MIRI的另一个标志物是肌酸激酶同工酶(CK-MB)的上调变化,但其具体范围并不清楚。
综上,现有的MIRI生物标记物不仅存在着种类受限,而且数量有限的标记物响应也是发生在心电图或影像学病理性观察结果的后期进程,患者一旦确诊MIRI,发生急性心肌梗死的风险已经很大、且病死率也高,这种心肌梗死病程后期的MIRI诊断,对于临床上快速干预急性的心肌梗死、降低高死亡风险的患者治疗形成了巨大的挑战。
鉴于现有技术存在的上述缺陷,亟需发明一种MIRI新标记物与高灵敏度检测、及其标记物代谢水平的调控技术。
发明内容
本发明的目的是提供一种心肌缺血再灌注损伤标记物。
本发明的另一个目的是提供上述心肌缺血再灌注损伤标记物代谢促进剂。
本发明的再一个目的是提供一种预防上述损伤的标记物代谢促进剂的应用。
本发明是通过以下技术方案实现的:
一种心肌缺血再灌注损伤标记物,为氧化态烟酰胺腺嘌呤二核苷酸(NAD+)。
本发明还提供了上述心肌缺血再灌注损伤标记物NAD+代谢促进剂,为中药来源的酚酸类成分,包括丹酚酸B、和/或α-β不饱和酚酸,其中所述的α-β不饱和酚酸包括阿魏酸、绿原酸、咖啡酸、迷迭香酸、或原儿茶酸。
上述心肌缺血再灌注损伤标记物,其代谢水平降低可用来诊断心肌缺血再灌注损伤及其诱导的心肌梗死,补充标记物代谢的促进剂可用于预防或治疗心肌缺血再灌注损伤、及其诱导的心肌梗死,尤其是可用于制备心肌缺血再灌注损伤及其心肌梗死的预防、治疗药物中。
本发明通过评价氧化还原态烟酰胺腺嘌呤二核苷酸(NAD+/NADH)体内代谢失衡、NAD+代谢物损耗量,建立心肌缺血再灌注损伤(MIRI)诱导心肌梗死与NAD+损耗水平的定量关系,发现MIRI病理过程和早期心肌梗死的新生物标记物NAD+;NAD+代谢促进剂为中药来源的酚酸类结构成分,包括丹酚酸B、和/或α-β不饱和酚酸等;NAD+代谢水平被促进剂上调,基于这种上调作用评价其对糖皮质(或盐皮质)类固醇激素类第一信使、以及对活性氧ROS(或环磷酸腺苷cAMP)第二信使的信号驱动,从而确定MIRI及其诱导的心肌梗死标记物NAD+、标记物代谢补充的促进剂。
与现有技术相比,本发明标记物NAD+代谢物水平具有预防DNA损伤、转录或翻译后修饰、表观调节、驱动信号转导、维持RNA稳定性及功能等多重生物学作用,是一种能够同时驱动第一信使和第二信使的信号转导,兼具调节过氧化物酶体、线粒体、核糖体和细胞核等重要细胞器的损伤压力,多途径预防、调节MIRI与心肌梗死的新型标记物分子,其NAD+代谢物及其防治MIRI作用的示意图如图1所示,其中,“←”和“ → ”分别表示抑制和激活作用,“ ↑”和“↓ ”表示升高和降低作用,糖皮质激素包括氢化可的松HYD、皮质酮CORT,盐皮质激素包括醛固酮ALD,ROS为活性氧自由基,cAMP为环磷酸腺苷。
通过标记物NAD+可进行MIRI诊断,且该诊断是针对发生在其诱导心肌梗死的早期、动态的病理阶段,可获得与正常心肌组织显现出显著性差异的阴性对照,与现有技术中采用的标记物种类及变化相比,在及时发现MIRI严重程度、降低心肌梗死高风险、确保患者生命健康等方面,更凸现临床防治的指导意义。
NAD+代谢物促进剂是来自中药活性成分的酚酸类结构化合物,可以促进NAD+代谢物体内合成、维持心肌氧化还原平衡和能量代谢稳态、进而提高心肌功能的高活性,高活性的中药成分是对现有NAD+代谢性补偿促进剂类型(如烟酸)的有益补充,也对采用NAD+代谢促进剂来应对MIRI诱导的心肌梗死具有积极的开发潜能。
综上所述,本发明心肌缺血再灌注损伤标记物NAD+是一种能够同时驱动第一信使和第二信使的信号转导,可多途径预防、调节MIRI与心肌梗死的新型标记物分子,对干预MIRI及其心肌梗死的药物研发有重要的指导意义。
附图说明
图1为NAD+代谢物及其防治MIRI作用的示意图;
图2 为实施例1中NAD+代谢物在MIRI大鼠体内的补充结果图;
图3为实施例2中NAD+对类固醇激素第一信使的代谢失活、及其对ROS、cAMP第二信使的表达调节作用图;
图4为实施例3中NAD+代谢促进剂对防治大鼠MIRI和心肌梗死作用图。
实施方式
以下结合实施例和附图对本发明作进一步说明。
实施例
采购6周龄SD健康大鼠,雄性,体重200±10克,适应性饲养3天,正常进食、饮水。将大鼠随机分为空白组和MIRI造模组,每组设6只,持续再饲养7天,期间每天经腹腔注射一次0.9%生理盐水。采用2%异氟烷气体麻醉大鼠,固定在实验台上,四肢连接心电图仪的电压感应器,颈部、胸部剪毛。MIRI造模采用左冠状动脉前降支结扎术,沿颈部正中部位剪开皮肤,用血管钳钝性分离皮下组织和气管上的肌肉,暴露气管。气管插管,打开人工呼吸机进行人工呼吸。沿胸骨正中剪开皮肤,紧贴胸骨左缘剪开第2、3根肋骨,打开心包膜、用7-0缝合线结扎左冠状动脉前降支2cm处、结扎30分钟,然后松开丝线再灌注24小时,完成造模。造模后在腹主动脉处取大鼠血清,同时取空白组的大鼠血清,用NAD+、NADH检测试剂盒(WST-8法)测定代谢物合成量,计算NAD+/NADH比值变化。运用GraphPad Prism8.3.0中单因素方差分析法,统计MIRI造模组与空白组之间的结果显著性差异。为确保模型成功,还须测量空白组和MIRI造模组的血清样中CTN-T和CK-MB变化,参照测定结果作为MIRI的现有标记物变化,评价NAD+作为MIRI新标记物以及测定方法的可靠性,并评价MIRI的显著性病理改变。
实施例
雄性大鼠分别经适应性、持续饲养3天和7天。随机设为空白组、MIRI造模组、术前阿托伐他汀补偿NAD+组(阳性组)、以及术前NAD+补偿促进剂(共设低、中、高 三个剂量)处理组,每组6支大鼠。阳性药、NAD补偿促进剂,是在持续饲养大鼠的期间每天腹腔注射给药一次。给药结束后,用左冠状动脉前降支结扎术,实施造模。分别取血清和心脏组织样品,处理、用NAD+、NADH检测试剂盒(WST-8法)测定组织中的代谢物合成变化,计算NAD+/NADH比值增加量;并用ELASA试剂盒分别检测血清和组织中的类固醇激素第一信使(包括氢化可的松HYD、皮质酮CORT、醛固酮ALD)的上调变化,用ELASA试剂盒检测血清中第二信使cAMP变化、以及用荧光探针检测心脏组织中的ROS。
实施例
体内实验,采用大鼠MIRI术前持续腹腔注射给药7天的实验方案。体外实验,用药物保护H9C2心肌细胞,随后进行缺糖缺氧处理。体内阳性药剂量采用10毫克/(千克体重·天),NAD+补充疗法采用的促进剂是酚酸类化合物,如丹酚酸B(Sal B)设低(L)、中(M)、高(H)剂量分别为5、10、20毫克/(千克体重·天)。大鼠实施MIRI手术,监测心脏心电图的ST段抬高变化与ST-T动态演变,再用超声心动图检测收缩期和舒张期左室前臂厚度(LVEF)、左室短轴缩短分数(LVFS)、射血分数(EF)、短轴缩短率(FS)等指标。然后在腹主动脉采血样,急性失血处死大鼠后取其心脏组织,检测血清学指标CTN-T和CK-MB、并用组织病理学HE切片染色、TTC染色分别观察心脏病理演变和心肌的梗死面积。体外实验,NAD+补充促进剂设低、中、高剂量组分别为5、10、20微摩尔/升,用显微观察比较缺糖缺氧型细胞与药物保护细胞之间的形貌变化。
NAD+代谢物在MIRI大鼠体内的补充结果如图2所示,图中Control,MIRI,Atorvastatin,Sal B/L,Sal B/M Sal B/H:空白对照大鼠,心肌缺血再灌注损伤大鼠,阿托伐他汀阳性药预处理大鼠组,丹酚酸B低、中、高剂量预处理大鼠组(n=6)。A):总NADH含量;B):还原型NADH含量;C):氧化型NAD+含量;D):NAD+/NADH比值;E)和F):NAD+补充对MIRI现有标记物CTN-T和CK-MB调节作用。
进一步地,NAD+对类固醇激素第一信使的代谢失活、及其对ROS、cAMP第二信使的表达调节作用如图3所示,图中Control,MIRI,Atorvastatin,Sal B/L,Sal B/M Sal B/H:空白对照大鼠,心肌缺血再灌注损伤大鼠,阳性药阿托伐他汀预处理大鼠组,丹酚酸B低、中、高剂量预处理大鼠组(n=3-6)。A):NAD+作为(酮式)氧化反应底物,失活类固醇激素的示意图;B):NAD+代谢物补充对MIRI大鼠血清中HYD激素的失活作用;C):NAD+代谢物补充对MIRI大鼠血清和心肌CORT激素的失活作用;D:)NAD+代谢物补充对MIRI大鼠血清和心肌ALD激素的失活作用;E):NAD+代谢物补充对第二信使ROS清除作用(荧光强度和统计图)。DHE为二氢乙锭超氧化物阴离子荧光探针,DAPI代表4',6-二脒基-2-苯基吲哚细胞核荧光染料;F):NAD+代谢物补充对第二信使cAMP激活作用。
再者,NAD+补充防治大鼠MIRI和心肌梗死的作用如图4所示,其中Control,MIRI,Atorvastatin,Sal B/L,Sal B/M Sal B/H:空白对照大鼠,心肌缺血再灌注损伤大鼠,阿托伐他汀阳性药预处理大鼠组,丹酚酸B低、中、高剂量预处理大鼠组(n=6)A):Sal B促进剂补充NAD+代谢物,对缺糖缺氧的H9C2心肌细胞形貌保护作用;B):各组大鼠心肌组织的苏木精-伊红(H&E)染色结果;C):各组大鼠心肌的TTC染色结果;D):各组大鼠心电图比较结果;E):各组大鼠超声心动图检查结果。
Claims (4)
1.一种心肌缺血再灌注损伤标记物,其特征在于,所述的标记物为NAD+。
2.权利要求1所述的心肌缺血再灌注损伤标记物代谢促进剂,其特征在于,所述的标记物代谢促进剂为中药来源的酚酸结构类成分,包括丹酚酸B、和/或酚酸结构类似物。
3.根据权利要求2所述的标记物代谢促进剂,其特征在于,所述的酚酸结构类似物为α-β不饱和酚酸,包括阿魏酸、绿原酸、咖啡酸、迷迭香酸、或原儿茶酸。
4.权利要求2或3所述的标记物代谢促进剂在制备预防或治疗心肌缺血再灌注损伤及其心肌梗死药物中的应用。
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