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|本期目录/Table of Contents|

血管钠肽抑制内质网应激减轻糖尿病大鼠缺血/再灌注心肌损伤

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2016年第6期
页码:
651-655
栏目:
基础研究
出版日期:
2016-07-05

文章信息/Info

Title:
Vasonatrin peptide inhibits endoplasmic reticulum stress and attenuates myocardial ischemia/reperfusion injury in diabetic rats
作者:
梁向艳1; 铁 茹1; 苏菲菲2; 于 军3; 朱妙章1; 张海锋1
（第四军医大学：1.教学实验中心，陕西 西安 710032，2.唐都医院心血管内科，陕西 西安 710038，4.生理学教研室，陕西 西安 710032；3.西安医学院第二附属医院中心实验室，陕西 西安 710004）
Author(s):
LIANG Xiang-yan1;  TIE Ru1;  SU Fei-fei2;  YU Jun3;  ZHU Miao-zhang4;  ZHANG Hai-feng1
(1.Experimental Teaching Centre, 4.Department of Physiology, Fourth Military Medical University, Xi’an 710032, Shaanxi, China；
2.Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, Shaanxi, China；
3.Central Laboratory, Second Affiliated Hospital, Xi’an Medical University, Xi’an 710004, Shaanxi, China)
关键词:
血管钠肽; 心肌缺血/再灌注损伤; 内质网应激; PKG; 糖尿病
Keywords:
vasonatrin peptide;  myocardial ischemia/reperfusion injury;  endoplasmic reticulum stress;  PKG;  diabetes
分类号:
R514
DOI:
-
文献标识码:
A
摘要:
目的 观察人工合成的钠尿肽——血管钠肽（VNP）对糖尿病（DM）大鼠心肌缺血/再灌注（MI/R）损伤的影响及机制。方法 高脂饲料喂养SD大鼠4周后，注射链脲霉素STZ（25 mg/kg,i.p.），1周后随机血糖≥11.1 mmol/L为DM模型构建成功，常规制备MI/R（30 min/4 h）模型。将大鼠随机分为4组：假手术组、MI/R组、DM+假手术组、DM+MI/R组。多导生理记录仪检测左室压上升/下降最大速率（±LVdP/dtmax），Evans blue-TTC双染色法检测心肌梗死面积，TUNEL法进行心肌细胞凋亡测试、试剂盒检测caspase-3活性，Western blot检测GRP78、Chop和PKG等蛋白表达。结果 与对照组相比，DM大鼠MI/R心肌损伤加重。VNP治疗（再灌前10 min，给予100 μg/kg,i.v）可显著减轻DM大鼠MI/R损伤，包括增强±LVdP/dtmax，降低心梗范围、死亡率与Caspase-3活性（n=8,P<0.05）。此外，VNP可降低内质网应激相关蛋白GRP78、CHOP表达（n=3,P<0.01）。VNP上述效应可同时被PKG阻断剂KT-5823（再灌前20 min，给予0.5 mg/kg,i.p）抑制、并被cGMP衍生物8-Br-cGMP（1 mg/kg）模拟（P<0.05，P<0.01）。用内质网应激抑制剂TUDCA（50 mg/kg）预处理DM大鼠，并不能增强VNP的心肌保护作用。结论 VNP治疗可减轻DM性MI/R损伤，其机制可能与通过cGMP-PKG信号抑制内质网应激有关，提示VNP对DM性缺血性心脏病具有潜在治疗价值。
Abstract:
AIM To investigate the effects of vasonatrin peptide (VNP) on myocardial ischemia/reperfusion (MI/R) injury in diabetic rats and to elucidate its mechanisms. METHODSHigh-fat diet and low-dose streptozotocin (STZ, 25 mg/kg, i.p.) injection induced diabetic Sprague Dawley rats with random blood glucose level >11.1 mmol/L 1 week later. Left anterior descending coronary artery was ligated for 30 min and reperfused for 4 h to establish the in vivo model of ischemia-reperfusion. RESULTSVNP treatment (100 μg/kg, i.v., 10 min before R) significantly improved ±LV dP/dtmax and LVSP and reduced LVEDP, apoptosis index, caspase-3 activity, plasma CK and LDH activities. Moreover, VNP inhibited endoplasmic reticulum (ER) stress by suppressing GRP78 and CHOP. These effects were mimicked by 8-Br-cGMP, a cGMP analogue but were inhibited by KT-5823, a selective inhibitor of PKG. In addition, pretreatment of DM rats with TUDCA, a specific inhibitor of ER stress, did not further promote the cardioprotective effect of VNP. CONCLUSIONVNP protects diabetic heart against MI/R injury by inhibiting ER stress via cGMP-PKG signaling pathway. These results suggest that VNP may have some potential therapeutic value for diabetic patients with ischemic heart disease.

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备注/Memo

备注/Memo:
收稿日期：2015-10-27.
基金项目：国家自然科学基金项目资助（81270330，31271220，81300190和81300077）；陕西省社会发展科技攻关项目资助（2014K11-02-03-02）
通讯作者：张海锋，副教授，主要从事心脏保护方面研究Email:hfzhang@fmmu.edu.cn
共同通讯作者：朱妙章，教授，主要从事钠尿肽方面研究Email:mz_zhu@fmmu.edu.cn
作者简介：梁向艳，实验师，硕士Email:liangxiangyan@126.com
更新日期/Last Update: 2016-07-10