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《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:

2015年第5期

页码:

501-505

栏目:

基础研究

出版日期:

2015-05-05

文章信息/Info

Title:

DCPIB attenuates myocardial ischemia/reperfusion injury through inhibiting autophagy in rat model

作者:

夏跃胜¹; 王 琳¹; 夏 桐²; 许 荣¹; 肖 远¹; 王 宁¹; 王晓明¹

（1.第四军医大学西京医院老年病科，陕西 西安 710032；
2.中山大学预防医学系，广东 广州 510080）

Author(s):

XIA Yue-sheng¹;  WANG Lin¹;  XIA Tong²;  XU Rong¹;  XIAO Yuan¹;  WANG Ning¹;  WANG Xiao-ming¹

(1.Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China；
2.Department of Preventive Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China)

关键词:

茚满酮复合物; 缺血/再灌注损伤; 血流动力学; 自噬

Keywords:

DCPIB;  ischemia/reperfusion injury;  hemodynamics;  autophagy

分类号:

R392.3

DOI:

-

文献标识码:

A

摘要:

目的 观察氯离子通道阻断剂茚满酮复合物(DCPIB)对在体大鼠缺血/再灌注(ischemia/reperfusion,I/R)心肌损伤的机制及心脏功能的影响。方法 雄性Sprague-Dawley(SD)大鼠36只随机分为6组:假手术组、I/R组、I/R+雷帕霉素(RAPA,4 mg/kg)组、I/R+DCPIB(10 mg/kg)组、I/R+3-甲基腺嘌呤(3MA，1 mg/kg)组和I/R+RAPA+DCPIB组。建立缺血30 min/再灌注24 h的大鼠I/R模型,于再灌注前10 min,经腹腔分别注射DCPIB、RAPA和3MA。检测再灌注前后血清肌酸激酶(CK)和肌酸激酶-同功酶(CK-MB)、核因子(NF)-κB和肿瘤坏死因子(TNF)-α活性，免疫组织化学检测自噬基因微管相关蛋白1的轻链3(LC3)表达，并记录心脏血流动力学指标。结果 ①与假手术组比较，I/R组自噬、炎症强度明显增加，心脏功能下降（P<0.05），RAPA组自噬进一步增加，心肌损害加重，而自噬抑制剂3MA可明显的抑制I/R和RAPA组心肌组织的自噬水平，减轻心肌损伤（P<0.05）；②与I/R组相比， DCPIB可明显抑制心肌损伤指标CK、CK-MB水平（P<0.05），抑制受损心肌组织中TNF-α、NF-κB活性、炎性细胞的浸润及LC3的表达（P<0.05）；DCPIB可明显改善心脏的血流动力学指标：左心室舒张末期压(LVEDP)下降，左室收缩压(LVSP)、左室内压上升的最大速率(+dp/dtmax)和左室内压下降的最大速率(-dp/dtmax)增加(P<0.05）；③与I/R+RAPA组相比，DCPIB同样抑制RAPA诱发心肌炎症和自噬水平增加，改善心脏功能。结论 DCPIB可通过抑制心肌组织的自噬和炎性反应，减轻心脏I/R损伤。

Abstract:

AIM To explore the possible mechanism of DCPIB (4-［(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy］ butanoic acid) in alleviating myocardial I/R injury. METHODS Sprague Dawley rats were randomly divided into sham operation group, I/R group, I/R+rapamycin (RAPA) group, I/R+DCPIB group, I/R+3-methyladenine (3MA, an autophagic inhibitor) group and I/R+RAPA+DCPIB group with six rats in each group. Ischemia was induced for 30 min followed by reperfusion for 24 h in rats. DCPIB (10 mg/kg), RAPA (4 mg/kg) and 3MA (1 mg/kg) were administered with intraperitoneal injection 10 min before the onset of reperfusion, respectively. Serum myocardial enzymes were measured and light microscopic study was performed. Myocardial LC3 was detected by immunohistochemistry. Nuclear factor-κB (NF-κB) and tumor necrosis factor α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS Expressions of myocardial LC3, TNFα and NF-κB significantly increased (P<0.05) and cardiac functions declined in I/R group compared with those in sham operation group (P<0.05). Myocardial LC3 further increased in RAPA group, which was reversed using 3MA, an autophagic inhibitor. Of note, DCPIB administration caused a significant reduction of myocardial LC3, TNF-α and NF-κB (P<0.05), significantly improved cardiac functional recovery and reduced myocardial enzyme activity compared with those in I/R group and I/R+RAPA+DCPIB group (P<0.05). Compared with those in sham-operated group, left ventricular systolic pressure (LVSP), maximal rate of ventricular pressure (+dp/dtmax) increased and maximal rate of ventricular pressure decreased (-dp/dtmax), whereas left ventricular end diastolic pressure (LVEDP) significantly increased in I/R group and I/R+RAPA group (P<0.05). DCPIB reversed the disorder. CONCLUSION Our results demonstrate that DCPIB attenuates myocardial ischemia/reperfusion injury through inhibiting autophagy.

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备注/Memo

备注/Memo:

收稿日期：2015-02-07.
基金项目：国家自然科学基金项目资助(81270169)
通讯作者：王晓明，教授，主要从事心血管疾病基础与临床研究 Email:xmwang@fmmu.edu.cn
作者简介：夏跃胜，主任医师，博士 Email:hsiayuer@fmmu.edu.cn

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更新日期/Last Update: 2015-04-28