丙戊酸钠对严重烫伤大鼠早期生存率和心肌损伤的作用及机制

Effects and mechanisms of sodium valproate on early survival and myocardial injury in rats with severe scald injury

  • 摘要:
    背景 丙戊酸钠(sodium valproate,VPA)在严重烫伤早期心脏功能保护研究中取得很大进展,缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)与心肌损伤密切相关,VPA与HIF-1α在严重烫伤心肌损伤中的作用机制仍有待探索。
    目的 研究VPA是否通过影响HIF-1α表达而减轻严重烫伤大鼠早期心肌损伤。
    方法 88只雄性SD大鼠随机分为假烫+ 0.9%氯化钠注射液组(NN组,n=24)、烫伤+ 0.9%氯化钠注射液组(SN组,n=32)、烫伤+ VPA组(SV组,n=32);采用沸水法致50%总体表面积Ⅲ度烫伤,伤后即刻,NN组、SN组腹腔内注射0.25 mL 0.9%氯化钠注射液,SV组腹腔内给予VPA治疗(300 mg/kg,溶于0.25 mL 0.9%氯化钠注射液)。分别于伤后3 h和6 h处死各组8只大鼠,取腹主动脉血,测定肌酸激酶同工酶(creatine kinase isoenzyme,CK-MB)水平;取心肌组织,观察心肌组织病理变化及凋亡心肌细胞,测定心肌组织内肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平,检测心肌组织内HIF-1α、BNIP3、裂解半胱氨酸天冬氨酸蛋白酶-3(Cleaved caspase-3)蛋白表达水平;各组剩余大鼠观察12 h生存情况。
    结果 生存分析显示,伤后12 h,SV组平均生存时间(550.00±17.32) min,生存率50%,优于SN组平均生存时间(400.00±29.76) min,生存率0(P<0.05)。与NN组比较,SN组伤后3 h和6 h的CK-MB、心肌细胞凋亡率、TNF-α、Cleaved caspase-3、HIF-1α和BNIP3蛋白表达均增加(P均<0.05);与SN组比较,SV组伤后CK-MB、心肌细胞凋亡率、TNF-α降低,Cleaved caspase-3、HIF-1α及BNIP3蛋白表达水平降低(P均<0.05);SV组病理损伤较SN组有所改善。
    结论 VPA能提高严重烫伤大鼠伤后早期生存率,减轻心肌损伤,可能与下调大鼠心肌组织内HIF-1α的表达有关。

     

    Abstract:
    Background Sodium valproate (VPA) has made great progress in the study of cardiac function protection in the early stage of severe scald injury, hypoxia-inducible factor-1α (HIF-1α) is closely related to myocardial injury, and the mechanism of action of VPA and HIF-1α in myocardial injury in severe scald injury remains to be explored.
    Objective To investigate whether VPA attenuates early myocardial injury in severely scalded rats by affecting HIF-1α expression.
    Methods Eighty-eight male SD rats were randomly divided into normal + 0.9% NaCl group (NN group, n=24), scald + 0.9% NaCl group (SN group, n=32), and scald + VPA group (SV group, n=32); Ⅲ ° scald with 50% of total surface area were caused by boiling water method, and NN and SN group were intraperitoneally injected with 0.25 mL of NaCl, and the SV group was intraperitoneally given VPA (300 mg/kg, dissolved in 0.25 mL of 0.9% NaCl) immediately after the injury. Eight rats in each group were executed at 3h and 6h after injury, and creatine kinase isoenzyme (CK-MB) levels were measured by taking blood from the abdominal aorta; myocardial tissues were taken for observation of myocardial tissue pathology and apoptotic cardiomyocytes, the levels of tumor necrosis factor-alpha (TNF-α), the expression levels of HIF-1α, BCL2/adenovirus E1B interacting protein 3 (BNIP3), and cleaved caspase-3; the 12-hour survival rate was observed in the remaining rats in each group.
    Results Survival analysis showed that at 12 h after injury, SV group had a mean survival time of (550.00±17.32) min and a survival rate of 50%, which were superior to that of SN group (mean survival time of 400.00±29.76 min and a survival rate of 0%, P < 0.05). Compared with NN group, CK-MB, cardiomyocyte apoptosis rate, TNF-α, cleaved caspase-3, HIF-1α, and BNIP3 protein expression levels increased in SN group at 3h and 6h post-injury (all P < 0.05); compared with SN group, CK-MB, cardiomyocyte apoptosis rate, TNF-α were decreased, and cleaved caspase-3, HIF-1α, and BNIP3 protein expression levels were decreased in SV group (all P < 0.05); pathologic injuries were improved in SV group compared to SN group.
    Conclusion VPA improves early post-injury survival and attenuates myocardial injury in severely scalded rats, which may be related to the down-regulation of HIF-1α expression in rat myocardial tissue.

     

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