载脂蛋白A-Ⅰ模拟肽通过抑制内质网应激改善肥胖合并心肌梗死大鼠的心功能

apoA-Ⅰmimetic peptide ameliorates cardiac function of obese rats with myocardial infarction by inhibitng endoplasmic reticulum stress

目的探讨载脂蛋白A-Ⅰ模拟肽左旋-氨基酸(L-4F)对肥胖合并心肌梗死大鼠心功能的影响及其可能机制。方法选择7周龄雄性SD大鼠60只,对照组12只大鼠给予普通饲料喂养,其余48只大鼠给予高脂饲料喂养8周,随机分为肥胖组,心肌梗死组,L-4F组,血红素氧化酶1(HO-1)抑制剂(SnMP)组,每组12只,后3组大鼠给予结扎冠状动脉左前降支,建立肥胖合并心肌梗死大鼠模型。干预8周后行超声心动图、血流动力学检查,包括左心室收缩末期内径(LVESD)、左心室舒张末期内径(LVEDD)、LVEF、左心室短轴缩短率(LVFS)、左心室收缩压(LVSP)、左心室舒张末压(LVEDP),计算左心室压力最大上升及下降速率(±dp/dt_(max)),组织标本采用苏木精-伊红染色和Masson染色,ELISA检测血清脂联素,实时荧光定量PCR和Western blot检测相关基因表达,包括内质网应激蛋白(Chop)、葡萄糖调节蛋白78(GRP78)及磷酸化类蛋白激酶内质网激酶(PERK)蛋白。结果与对照组比较,肥胖组LVESD、LVEDD、LVSP、LVEDP、Chop及磷酸化PERK明显升高,LVEF、LVFS、-dp/dt_(max)、HO-1、脂联素水平明显降低;与心肌梗死组比较,L-4F组LVESD、LVEDD、LVSP、LVEDP、Chop、GRP78及磷酸化PERK明显降低,LVEF、LVFS、±dp/dt_(max)、HO-1、脂联素明显升高(P<0.05,P<0.01);与L-4F组比较,SnMP组LVESD、LVEDD、LVSP、LVEDP明显升高,Chop、GRP78及磷酸化PERK明显升高[1.14±0.15 vs 0.80±0.09,P<0.05;5.04±0.33 vs 2.96±0.22,P<0.05;16.79±0.89 vs 5.18±0.73,P<0.01],LVEF、LVFS、±dp/dt_(max)、HO-1、脂联素水平明显降低(P<0.05,P<0.01)。结论L-4F通过激活肥胖合并心肌梗死大鼠HO-1-脂联素轴,抑制内质网应激,降低心肌细胞毒性,抑制心脏重构,改善大鼠心功能。

Objective To investigate the effects and possible mechanism of apolipoprotein A-Ⅰmimetic peptide,L-amino acid(L-4 F)on post-infarction cardiac function of obese rats.Methods Sixty male 7-week-old SD rats were randomly and equally divided into control group and 5 experimental groups.The rats in control group were given normal chow diet and sham operation and ABC buffer,while those in other groups were given high-fat diet for 8 weeks,and then randomized into obesity group,MI group,L-4 F group,and HO-1 inhibitor SnMP group,with 12 rats in each group.The latter 3 groups of rats were subjected to left anterior descending coronary artery ligation to establish a model of obese rats with MI.After 8 consecutive weeks,cardiac structure and function were examined under the anesthetized state by echocardiography and hemodynamic assessment for LVESD,LVEDD,LVEF,LVFS,LVSP,LVEDP,±dp/dt_(max).HE and Masson trichrome stainings were used for myocardial histological observation.The serum adiponectin level was measured by ELISA.Real-time fluorescence quantitative PCR and Western blotting were also applied in measuring the mRNA and protein levels of Chop,GRP78 and p-PERK.Results Compared with the control group,the obesity group showed significantly higher levels of LVESD,LVEDD,LVSP,LVEDP,Chop and p-PERK,lower levels of LVEF,LVFS,-dp/dt_(max),HO-1 and adiponectin.The L-4 F group had obviously lower levels of LVESD,LVEDD,LVSP,LVEDP,Chop,GRP78 and p-PERK,higher levels of LVEF,LVFS,±dp/dt_(max),HO-1 and adiponectin than the MI group(P<0.05,P<0.01).SnMP treatment resulted in remarkably increased levels of LVESD,LVEDD,LVSP,LVEDP,enhanced expression of Chop,GRP78 and p-PERK(1.14±0.15 vs 0.80±0.09,P<0.05;5.04±0.33 vs 2.96±0.22,P<0.05;16.79±0.89 vs 5.18±0.73,P<0.01),and reduced levels of LVEF,LVFS,±dp/dt_(max),HO-1 and adiponectin(P<0.05,P<0.01)when compared with the L-4 F group.Conclusion Through activation of HO-1/adiponectin axis,L-4 F inhibits endoplasmic reticulum stress,reduces cardiomyocyte toxicity,supresses cardiac remodeling,and ameliorates cardiac function in obese MI rats.