载脂蛋白A-Ⅰ模拟肽对肥胖大鼠心脏结构和功能的影响及可能机制研究

Effect of apoA-Ⅰmimetic peptide on cardiac function in obese rats and its mechanism

目的探讨载脂蛋白A-Ⅰ模拟肽(L-4F)对肥胖大鼠心功能的影响及可能机制。方法 50只SD大鼠中,随机选择10只喂食普通饲料为对照组,另40只喂食高脂饲料8周后,肥胖模型造模成功率75%,将肥胖模型成功大鼠30只再随机分为肥胖组、诱导剂组[血红素氧合酶1(HO-1)诱导剂L-4F]和抑制剂组(HO-1抑制剂SnMP),每组10只,各组每天腹腔注射相应药物,持续8周。心脏超声和血流动力学检测后,自腹主动脉取血,ELISA检测各项指标。苏木精-伊红染色观察心肌组织病理变化;分别用RT-PCR和Western blot测心肌组织HO-1、脂联素基因和蛋白表达。结果与对照组比较,肥胖组和抑制剂组干预8周体质量较基线体质量增加显著升高(P<0.01),血糖、胰岛素、TNF-α、白细胞介素6和丙二醛水平明显升高(P<0.05,P<0.01),胆红素、超氧化物歧化酶[(3.26±0.51)μg/L和(5.90±0.49)μg/L vs (8.66±0.70)μg/L,P<0.05,P<0.01]和脂联素水平明显降低[(4.16±0.75)μg/L和(4.62±0.52)μg/L vs (6.72±1.09)μg/L,P<0.05],诱导剂组上述指标无明显变化(P>0.05);肥胖组和抑制剂组左心室舒张末期内径、左心室收缩末期内径显著增大(P<0.01),左心室短轴缩短率和LVEF及左心室最大压力最大变化速率显著降低(P<0.05,P<0.01),肥胖组左心室收缩压和左心室舒张末压明显升高(P<0.01),而诱导剂组上述指标则无明显变化(P>0.05)。肥胖组和抑制剂组心肌组织HO-1和脂联素mRNA和蛋白表达较对照组明显减低(P<0.05,P<0.01);诱导剂组HO-1和脂联素蛋白表达显著高于肥胖组和抑制剂组(P<0.01);而抑制剂组与肥胖组HO-1和脂联素蛋白表达无显著差异(P>0.05)。苏木精-伊红染色显示,肥胖组心肌细胞肥大、充血,心肌细胞间有较明显的纤维条索形成,慢性炎性反应明显,抑制剂组心肌组织也有较明显的充血、心肌细胞肥大,纤维条索形成,但是较肥胖组减轻;诱导剂组与对照组相似。结论 L-4F上调肥胖大鼠HO-1与脂联素轴,降低肥胖大鼠体质量,减轻胰岛素抵抗和炎性反应,改善氧化应激状态,抑制心肌重构,改善肥胖大鼠的心功能。

Objective To study the effect of apo A-Ⅰmimetic peptide(L-4 F)on cardiac function in obese rats and its mechanism.Methods Fifty SD rats were randomly divided into control group,obesity group,inducer group,inhibitor HO-1 group and inhibitor SnMP group(10 in each group)after the obesity model was established.The rats in different groups received intraperitoneal injection with relative drugs for 8 weeks.Myocardial tissue samples were taken and stained with HE for observing the pathological change of myocardial tissue.The expressions of HO-1 and adiponectin protein were detected by RT-PCR and Western blot respectively.Results The serum levels of blood glucose,insulin,TNF-α,IL-6 and MDA were significantly higher(P<0.05,P<0.01)while those of bilirubin and adiponectin were significantly lower in obesity group and two inhibitor groups than in control group(3.26±0.51μg/L and 5.90±0.49μg/L vs 8.66±0.70μg/L,P<0.05,P<0.01;4.16±0.75μg/L and 4.62±0.52μg/L vs 6.72±1.09μg/L,P<0.05).No significant difference was detected in serum levels of blood glucose,insulin,TNF-α,IL-6,MDA,bilirubin and adiponectin in inducer group(P>0.05).The LVEDD and LVSDD were significantly longer while the LVFS,LVFE,and +dp/dtmaxwere significantly lower in obesity group and two inhibitor groups than in control group(P<0.05,P<0.01).The LVSBP and LVEDP were significantly higher in obesity group than in control group(P<0.01).The expression levels of HO-1 and adiponectin mRNA and protein were significantly lower in obesity group and two inhibitor groups than in control group(P<0.05,P<0.01)and were significantly higher in inducer group than in obesity group and two inhibitor groups(P<0.01).No significant difference was detected in expressions of HO-1 and adiponectin between two inhibitor groups and obesity group(P>0.05).HE staining showed more hypertrophic and congestive cardiomyocytes,more formation of fibroid cords,and more significant chronic inflammatory reactions in obesity group and two inhibitor groups than in control group.Conclusion L-4 Fcan increase the HO-1 and adiponectin axis,reduce the BMI,alleviate the insulin resistance and inflammation reactions,inhibit the myocardial remodeling under oxidized stress,and improve the cardiac function in obese rats.