CN109999029B - N6022在治疗糖尿病外周动脉疾病中的医药用途 - Google Patents
N6022在治疗糖尿病外周动脉疾病中的医药用途 Download PDFInfo
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Abstract
N6022在治疗糖尿病外周动脉疾病中的医药用途，涉及在心血管领域。在动物水平，在糖尿病小鼠侧肢缺血模型中，尾静脉注射N6022能改善血流恢复，增加骨骼肌的血管新生，改善糖尿病外周动脉疾病。在细胞水平，给予GSNOR抑制剂N6022能改善高糖导致的人脐静脉内皮细胞（HUVEC）迁移能力和成管能力的降低。本发明开拓了N6022一个新的应用领域，对于治疗糖尿病外周动脉疾病，改善糖尿病血管病变状况提供了有意义的参考。
Description
技术领域
本发明属于糖尿病外周动脉疾病技术领域，具体涉及亚硝基谷胱甘肽还原酶（GSNOR）抑制剂N6022的应用，尤其涉及在制备治疗糖尿病外周动脉疾病（PAD）药物中的应用。
背景技术
下肢外周动脉疾病（PAD）具有高患病率，在糖尿病人群中达20%～40%，随着年龄的增加，糖尿病者患PAD的风险增加2～4倍，是最重要的危险因素。PAD具有高致残率和死亡率，PAD导致的下肢动脉狭窄、闭塞引起严重肢体缺血（CLI），血管新生减少及侧枝循环形成障碍等因素引起的伤口愈合迟缓，不仅是糖尿病足发生的危险因素之一，还是导致糖尿病足患者截肢的独立危险因素之一，更重要的是PAD可增加患者心血管事件发生风险和病死率，PAD患者在确诊1年后心血管事件发生率高达21.14%，与已发生心脑血管病变者再次发作风险相当。因此，PAD具有发病率高、危害大、可防治难的特征，找寻新的有效的治疗外周血管病变（PAD）方法是临床上有效降低其致残率、致死率的关键。
亚硝基谷胱甘肽还原酶（S-nitrosoglutathionereductase, GSNOR）作为醇脱氢酶家族中一个特殊的蛋白酶，其在细胞内的主要作用是调节亚硝基谷胱甘肽（S-nitrosoglutathione, GSNO）的代谢，进而影响着细胞内一氧化氮（Nitric oxide, NO）的稳态调节。亚硝基谷胱甘肽还原酶（GSNOR）抑制剂N6022是一种特异的可逆的亚硝基谷胱甘肽还原酶抑制剂，研究表明N6022能够有效改善哮喘及过敏性气道炎症，并且N6022作为治疗慢性哮喘和囊性纤维病的一期、二期临床实验已经完成。近期有文献报道，N6022对治疗自身免疫性脑脊髓炎（EAE）也有一定疗效。但是N6022是否能够改善糖尿病外周动脉疾病（PAD）及其机制目前尚未有任何相关的研究和报道。
发明内容
解决的技术问题：本发明提供一种N6022在治疗糖尿病外周动脉疾病中的医药用途，通过抑制GSNOR的活性，从而有效改善糖尿病外周动脉疾病。该方法包含给糖尿病侧肢缺血模型小鼠尾静脉注射N6022，以及利用N6022抑制人脐静脉内皮细胞（HUVEC）中GSNOR的活性。
技术方案: GSNOR作为标志物在制备治疗糖尿病外周动脉疾病（PAD）药物试剂盒中的应用。
GSNOR作为标志物在筛选治疗糖尿病外周动脉疾病（PAD）药物中的应用。
抑制GSNOR表达的抑制剂N6022在制备治疗糖尿病外周动脉疾病（PAD）药物中的应用。
有益效果：给糖尿病侧肢缺血模型小鼠尾静脉注射N6022，可有效改善缺血侧肢的血流恢复，从而起到治疗糖尿病外周血管疾病（PAD）的效果；利用N6022抑制人脐静脉内皮细胞（HUVEC）GSNOR的活性，可有效改善由高糖引起的内皮细胞迁移、成管能力的降低。
附图说明
图1为激光散斑血流成像系统监测侧肢的血流恢复情况图，其中a:通过构建糖尿病小鼠侧肢缺血模型，术后分别尾静脉注射对照溶剂DMSO，以及不同浓度的N6022（0.01mg/kg/day，0.1mg/kg/day，1mg/kg/day）, 激光散斑血流成像系统监测右侧结扎侧肢的血流恢复情况；b:结扎侧肢血流灌注比统计（缺血侧肢/正常侧肢）。*与糖尿病小鼠注射对照溶剂DMSO的实验组相比*<0.05。
图2为对小鼠缺血侧肢的腓肠肌进行冰冻切片，免疫荧光（CD31）检测血管新生结果图，其中a:通过对小鼠腓肠肌冰冻切片，免疫荧光（CD31）检测血管新生情况；b:新生血管面积量化图。*与未造糖尿病模型注射对照溶剂DMSO的对照组相比*<0.05,#与糖尿病小鼠注射对照溶剂DMSO的实验组相比#<0.05。
图3为对小鼠缺血侧肢的半膜肌进行冰冻切片，免疫荧光（α-SMA）检测动脉生成结果图，其中a:通过对小鼠半膜肌冰冻切片，免疫荧光（α-SMA）检测动脉生成情况；b:新生小动脉面积量化图。*与未造糖尿病模型注射对照溶剂DMSO的对照组相比*<0.05,#与糖尿病小鼠注射对照溶剂DMSO的实验组相比#<0.05。
图4为分离造模小鼠的主动脉进行主动脉环出芽（Aortic ring assay）实验结果图，其中a:通过提取小鼠主动脉内皮，主动脉环出芽（Aortic ring assay）实验检测出芽能力；b:动脉出芽面积量化图。*与未造糖尿病模型注射对照溶剂DMSO的对照组相比*<0.05,#与糖尿病小鼠注射对照溶剂DMSO的实验组相比#<0.05。
图5为成管实验结果图，其中 a:通过对人脐静脉内皮细胞（HUVEC）高糖（HG）处理24h，给予不同浓度（1nM、10nM、100nM）的N6022，甘露醇为高渗对照，检测HUVEC成管能力；b:成管面积量化图。*与未加高糖（HG）处理的对照组相比p<0.05，#与相同浓度高糖（HG）处理但未给予N6022的实验组相比#<0.05。
图6为划痕实验结果图，其中 a:通过对人脐静脉内皮细胞（HUVEC）高糖（HG）处理，给予N6022（10nM），甘露醇为高渗对照，划痕实验检测HUVEC细胞的迁移能力；b:迁移面积量化图。*与未加高糖（HG）处理的对照组相比p<0.05，#与相同浓度高糖（HG）处理但未给予N6022的实验组相比#<0.05。
图7为Transwell实验结果图，其中a:通过对人脐静脉内皮细胞（HUVEC）高糖（HG）处理，给予N6022（10nM），甘露醇为高渗对照，Transwell实验检测HUVEC细胞的迁移能力；b:细胞迁移量比率量化图。*与未加高糖（HG）处理的对照组相比p<0.05，#与相同浓度高糖（HG）处理但未给予N6022的实验组相比#<0.05。
图8为球体出芽（Spheroid capillary sprouting assay）实验结果图，其中 a:通过对人脐静脉内皮细胞（HUVEC）高糖（HG）处理，给予N6022（10nM），甘露醇为高渗对照，球体出芽（Spheroid capillary sprouting assay）实验检测HUVEC细胞的迁移能力；b:出芽面积量化图。*与未加高糖（HG）处理的对照组相比p<0.05，#与相同浓度高糖（HG）处理但未给予N6022的实验组相比#<0.05。
具体实施方式
以下实施例进一步说明本发明的内容，但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下，对本发明方法、步骤或条件所作的修改和替换，均属于本发明的范围。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。以下实施例中所使用的试剂和材料均为市售产品。实例中所用N6022为市售产品，购买于selleck.cn。
实施例1：N6022对糖尿病侧肢缺血模型小鼠侧肢缺血情况的改善作用
为了探索N6022对糖尿病侧肢缺血模型小鼠侧肢缺血情况的影响，我们选用了SPF级8周雄性C57BL/6小鼠（购于南京医科大学医药实验动物中心），随机分为五组：溶剂对照组，糖尿病模型溶剂对照组及三个不同N6022浓度（0.01mg/kg/day、0.1mg/kg/day、1mg/kg/day）糖尿病模型给药组。其中糖尿病模型是在小鼠8周时，通过连续5天腹腔注射链脲霉素（STZ）60mg/kg/day，10周时测血糖>16.6 mmol/L，所有组别小鼠在11周造侧肢缺血模型，术后通过尾静脉注射不同浓度的N6022（0.01mg/kg/day、0.1mg/kg/day、1mg/kg/day）以及对照溶剂DMSO，分别在第0、7、14天通过激光散斑血流成像系统监测侧肢的血流恢复情况。并且分离小鼠缺血侧肢的腓肠肌进行冰冻切片，免疫荧光（CD31）检测血管新生情况；分离半膜肌进行冰冻切片，免疫荧光（α-SMA）检测动脉生成情况。同时我们分离了造模小鼠的主动脉进行主动脉环出芽（Aortic ring assay）实验检测出芽能力从而反映血管新生状况。
图1激光散斑血流成像系统监测侧肢的血流恢复情况结果表明，在糖尿病小鼠尾静脉注射不同浓度的N6022（0.01mg/kg/day、0.1mg/kg/day、1mg/kg/day）的第7天和第14天，缺血侧肢的血流灌注量均明显高于糖尿病小鼠，缺血情况得到改善。
图2对小鼠缺血侧肢的腓肠肌进行冰冻切片，免疫荧光（CD31）检测血管新生，结果显示，给药组（N6022 0.1mg/kg/day）血管新生情况较于糖尿病模型小鼠得到明显改善。
图3 对小鼠缺血侧肢的半膜肌进行冰冻切片，免疫荧光（α-SMA）检测动脉生成，结果显示，给药组（N6022 0.1mg/kg/day）动脉生成明显高于糖尿病模型小鼠。
图4分离造模小鼠的主动脉进行主动脉环出芽（Aortic ring assay）实验，结果显示，给药组（N6022 0.1mg/kg/day）小鼠的主动脉出芽能力明显高于糖尿病模型小鼠。
实施例2：N6022对由高糖引起的内皮细胞迁移、成管能力降低的改善作用
已知在糖尿病外周动脉疾病（PAD）中，血管新生减少是引起局部严重缺血继而发生溃疡、截肢的危险因素之一，为了研究GSNOR抑制剂N6022对高糖引起的内皮细胞功能受损的作用，所以我们在细胞水平通过成管实验检测血管生成能力，将HUVEC（2*10^4）种至凝好的Matrigel的24孔板中，通过给予不同浓度的N6022（1nM、10nM、100nM），甘露醇组为高糖的等渗对照，24h后检测血管生成情况。并且我们通过划痕实验、transwell实验、球体出芽（Spheroid capillary sprouting assay）实验检测内皮细胞的迁移能力，以上实验均说明N6022能明显逆转由高糖引起的内皮细胞迁移、成管能力的下降。
图5成管实验结果表明，在给予较低浓度的N6022（1nM、10nM、100nM）后，HUVEC细胞的成管能力较于单纯给予高糖刺激明显改善，其中给予10nM N6022处理细胞后，内皮细胞的成管能力恢复更显著。
图6划痕实验结果表明，高糖处理下，在给予N6022（10nM）后，HUVEC细胞的迁移能力得到改善。
图7Transwell实验结果表明，在给予N6022（10nM）后，HUVEC的细胞迁移量较于高糖组明显增加，细胞迁移能力得到恢复。
图8球体出芽（Spheroid capillary sprouting assay）实验结果表明，高糖刺激HUVEC细胞出芽能力明显降低，而在给予N6022（10nM）后细胞出芽能力增加，迁移能力改善。
Claims (1)
1.抑制亚硝基谷胱甘肽还原酶表达的抑制剂
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