阿昔莫司对脂多糖诱导脓毒症大鼠心肌损伤及Nrf2/HO-1信号通路的影响

Effects of Acipimox on Cardiac Injury and Nrf2/HO-1 Signaling Pathway in Lipopolysaccharide-induced Sepsis Rats

目的:探讨阿昔莫司对脂多糖诱导的脓毒症大鼠心肌损伤及核因子E2相关因子2(Nrf2)/血红素加氧酶-1(HO-1)信号通路的影响。方法:将50只SD大鼠分为正常对照组、模型组、阿昔莫司组、Nrf2通路抑制剂全反式维甲酸组(ATRA组)、阿昔莫司+ATRA组,每组10只。通过腹腔注射脂多糖(5 mg/kg)建立脓毒症大鼠模型。检测并比较各组大鼠一般状况、血清心肌损伤标志物、血脂水平变化、心肌组织氧化应激及炎症因子水平、心肌组织病理改变、心肌细胞凋亡与细胞核中Nrf2表达情况,以及HO-1、核因子-κB(NF-κB)、磷酸化NF-κB(p-NF-κB)、脂蛋白脂肪酶(LPL)、超氧化物歧化酶2(SOD2)、过氧化氢酶(CAT)、A类清道夫受体(SR-A)、过氧化物酶体增殖物激活受体α(PPARα)蛋白表达。结果:与模型组比较,阿昔莫司组大鼠无死亡,多呼吸较为平缓,精神萎靡症状缓解,心肌组织病理损伤缓解,心肌细胞凋亡率、血清肌酸激酶、乳酸脱氢酶、心肌肌钙蛋白Ⅰ、甘油三酯、游离脂肪酸及心肌组织中丙二醛、活性氧簇、白细胞介素-6、肿瘤坏死因子-α水平均降低,血清中总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇水平升高,同时心肌组织的细胞核中Nrf2阳性表达及其下游HO-1、SOD2、CAT、SR-A、PPARα蛋白表达进一步升高,但p-NF-κB/NF-κB、LPL蛋白表达降低(P均<0.05);此外,阿昔莫司+ATRA组对脓毒症大鼠的作用效果介于ATRA组和阿昔莫司组之间,ATRA减弱了阿昔莫司对脓毒症大鼠上述指标的影响(P均<0.05)。结论:阿昔莫司能激活Nrf2/HO-1通路介导的抗炎、抗氧化应激及抗脂质代谢异常等途径,缓解脂多糖诱导的脓毒症大鼠心肌氧化应激、炎症、脂质堆积等引起的损伤。

Objectives:To investigate the effect of acipimox on cardiac injury and nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)pathway in lipopolysaccharide(LPS)-induced sepsis rats.Methods:SD rats were divided into normal control group,model group,acipimox group,Nrf2 pathway inhibitor all-trans retinoic acid(ATRA)group,and acipimox+ATRA group,with 10 rats in each group.A rat model of sepsis was established by intraperitoneal injection of LPS(5 mg/kg).The general condition,serum myocardial injury markers,change of blood lipid levels,myocardial tissue oxidative stress and inflammatory factor levels,myocardial tissue pathological change,myocardial apoptosis and Nrf2 expression in the nucleus,as well as the protein expression of HO-1,nuclear factor-κB(NF-κB),phosphorylated NF-κB(p-NF-κB),lipoprotein lipase(LPL),superoxide dismutase 2(SOD2),catalase(CAT),class A scavenger receptor(SR-A),peroxisome proliferator-activated receptorα(PPARα)in rats of each group were detected and compared.Results:Compared with the model group,the rats in the acipimox group did not die,and most of the rats had relatively smooth breathing,the symptoms of mental apathy were relieved,the pathological damage of myocardial tissue was relieved,the apoptosis rate of myocardial cells,and the levels of creatine kinase,lactate dehydrogenase,cardiac troponin I,triglyceride,free fatty acid in serum and malondialdehyde,reactive oxygen species,interleukin-6 and tumor necrosis factor-αin myocardial tissue decreased,the levels of total cholesterol,high-density lipoprotein cholesterol and low density lipoprotein cholesterol in serum increased,and the positive expression of Nrf2 in the nucleus of myocardial tissue and the protein expressions of its downstream HO-1,SOD2,CAT,SR-A and PPARαwere further increased,but the expressions of p-NF-κB/NF-κB and LPL proteins were decreased(all P<0.05);in addition,the effect of acipimox+ATRA group on the sepsis rats was between that of the ATRA group and the acipimox group,and it weakened the effect of acipimox on the above indicators in sepsis rats(all P<0.05).Conclusions:Acipimox can activate the Nrf2/HO-1 pathway-mediated anti-inflammatory,anti-oxidative stress and antilipid metabolism abnormalities,and alleviate LPS-induced damage caused by heart oxidative stress,inflammation,and lipid accumulation in sepsis rats.