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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≥11.1mmol/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(±LVd P/dtm ax),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100μg/kg,i.v)可显著减轻DM大鼠MI/R损伤,包括增强±LVd P/dtm ax,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c GMP衍生物8-Br-c GMP(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c GMP-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。
Objective To observe the effect and mechanism of artificial synthetic natriuretic peptide - vascular natriuretic peptide (VNP) on myocardial ischemia / reperfusion (MI / R) injury in diabetic rats. Methods SD rats were injected with streptozotocin STZ (25 mg / kg, ip) after 4 weeks of high-fat diet. After 1 week, the random blood glucose of 11.1 mmol / L was established as DM model. The routine preparation of MI / R min / 4 h) model. The rats were randomly divided into 4 groups: sham operation group, MI / R group, DM + sham operation group, DM + MI / R group. (± LVd P / dtm ax), myocardial infarct size by Evans blue-TTC double staining method, cardiomyocyte apoptosis test by TUNEL method and caspase-3 Activity, Western blot detection of GRP78, Chop and PKG protein expression. Results Compared with the control group, the MI / R myocardial injury in DM rats was aggravated. Treatment with VNP (100 μg / kg, iv 10 min before reperfusion) significantly reduced MI / R injury in DM rats, including increased ± LVd P / dtm ax, decreased myocardial infarct size, mortality and Caspase-3 activity = 8, P <0.05). In addition, VNP decreased the expression of endoplasmic reticulum stress-related proteins GRP78 and CHOP (n = 3, P <0.01). The effect of VNP was inhibited both by PKG blocker KT-5823 (given at 0.5 mg / kg ip 20 minutes before reperfusion) and was simulated by cGMP derivative 8-Br-c GMP (1 mg / kg) P <0.05, P <0.01). Pretreatment of DM rats with endoplasmic reticulum stress inhibitor TUDCA (50 mg / kg) did not enhance myocardial protection by VNP. Conclusion VNP treatment can reduce the DM MI / R injury, and its mechanism may be related to inhibition of endoplasmic reticulum stress by c-GMP-PKG signaling, suggesting that VNP has potential therapeutic value for DM ischemic heart disease.