Omega-3多不饱和脂肪酸对妊娠期糖尿病模型大鼠子代心脏功能及索拉菲尼激酶/丝裂原激活蛋白激酶/细胞外信号调节激酶通路的影响

Impacts of Omega-3 polyunsaturated fatty acids on cardiac function and sorafenib kinase/mitogen-activated protein kinase/extracellular signal-regulated kinase pathway of offspring of gestational diabetes mellitus model rats

目的探讨Omega-3多不饱和脂肪酸(Omega-3)对妊娠期糖尿病(GDM)模型大鼠子代心脏功能的影响及机制。方法取70只受孕大鼠中的10只,腹腔注射柠檬酸缓冲液+正常饲料喂养作为正常组;剩余60只中有50只GDM造模成功,分别设置为模型组、阳性药组及Omega-3低、中、高剂量组,每组10只,将Omega-3按照200mg/(kg·d)、400mg/(kg·d)、800mg/(kg·d)的剂量以10mL/kg的分别给Omega-3低、中、高剂量组灌胃,阳性药组注射胰岛素20U/(kg·d),模型组、正常组以等量生理盐水灌胃,各组均从妊娠第5天开始给药至分娩。观察各组分娩情况,取子代成年雄性大鼠的离体心脏检测心功能变化、心肌梗死面积、索拉菲尼激酶(Raf)/丝裂原激活蛋白激酶(MEK)/细胞外信号调节激酶(ERK)通路的磷酸化蛋白、胰高血糖素样肽-1(GLP-1)蛋白的表达。结果与正常组相比,模型组孕鼠所产乳鼠只数及乳鼠成活只数减少;与模型组相比,Omega-3低、中、高剂量组及阳性药组孕鼠所产乳鼠只数及乳鼠成活只数均有所增加。与模型组相比,Omega-3低、中、高剂量组及阳性药组子代成年雄性大鼠心率(HR)、冠脉流量(CF)、左室收缩压(LVSP)均升高,左室舒张末压(LVEDP)降低,心肌梗死面积减小,心肌组织p-Raf/Raf、p-MEK/MEK、p-ERK/ERK及GLP-1蛋白表达水平均升高(P<0.05),且与Omega-3剂量有关。结论GDM模型大鼠孕期给予Omega-3灌胃可激活子代成年雄性大鼠Raf/MEK/ERK通路及GLP-1的表达,提高其心功能,增强大鼠对缺血/再灌注损伤的耐受性,降低子代罹患先天性心脏病(CHD)的风险。

Objective To investigate the impact and mechanism of Omega-3 polyunsaturated fatty acids(Omega-3) on the cardiac function of offspring of gestational diabetes mellitus(GDM) model rats. Methods 10 out of 70 pregnant rats were taken and given intraperitoneal injection of citrate buffer solution+normal feed as the normal group;50 of the rest 60 pregnant rats were successfully modeled, and were set as the model group, the Omega-3 low, medium, and high dose groups, and the positive drug group, with 10 rats in each group. The Omega-3 low, medium and high dose groups were given 10 mL/kg of Omega-3 by intragastric administration at the doses of 200 mg/(kg·d), 400 mg/(kg·d) and 800 mg/(kg·d), respectively. The positive drug group was injected with insulin 20 U/(kg·d). The model group and the normal group were given the same amount of normal saline by intragastric administration. All groups were administered from the 5 th day of pregnancy until delivery. The delivery situation of each group was observed. Cardiac function, myocardial infarction size, and expression of sorafenib kinase(Raf)/mitogen-activated protein kinase(MEK)/extracellular signal-regulated kinase(ERK) pathway phosphorylated protein and glucagon-like peptide-1(GLP-1) were measured in isolated adult male rat hearts. Results Compared with the normal group, the number of neonatal rats and the number of surviving neonatal rats in the model group were fewer. Compared with the model group, the number of neonatal rats and the number of surviving neonatal rats in the Omega-3 low, medium and high dose groups and the positive drug group increased. Compared with the model group, the heart rate(HR), coronary flow(CF) and left venteicular systolic pressuer(LVSP) of the offspring adult male rats in the Omega-3 low, medium and high dose groups and the positive drug group were all increased, left ventricular end diastoli pressure(LVEDP) decreased, myocardial infarction size decreased, the protein expression levels of p-Raf/Raf, p-MEK/MEK, p-ERK/ERK and GLP-1 in myocardial tissue were all increased(P<0.05), and were related to the dose of Omega-3. Conclusions Intragastric administration of Omega-3 in GDM model rats during pregnancy can activate Raf/MEK/ERK pathway and the expression of GLP-1 in adult male offspring rats, improve their cardiac function of offspring, enhance the tolerance of rats to ischemia/reperfusion injury, and reduce the risk of congenital heart disease(CHD) in offspring.