白毛黑眼兔与日本大耳白兔胰岛素抵抗动脉粥样硬化模型的比较
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摘要
目的探讨白毛黑眼(WHBE)兔和日本大耳白(JW)兔胰岛素抵抗动脉粥样硬化(insulin resistance atherosclerosis,IR-AS)模型的表型差异和病理机制。方法取WHBE兔与JW兔各12只,分为正常对照组(NC)和高脂高糖饮食(HF)组,每组6只。用HF饮食12周诱发IR-AS模型。造模结束后,取血测定血脂、超氧化物歧化酶(SOD)和丙二醛(MDA)水平;行糖耐量试验,计算血糖和胰岛素曲线下面积;检测肝微粒体甘油三酯转运蛋白(MTTP)、核因子E2(Nrf2)和SOD1基因的表达,并观察脂肪和主动脉血管的HE染色病理变化以及血管CD68的表达情况。结果与NC组比,HF组肥胖,血脂升高,糖耐受不良,高胰岛素血症和胰岛素抵抗指数(HOMA-IR)明显升高,血浆及肝SOD活性下降且MDA含量升高,肝MTTP和Nrf2基因表达升高且SOD1基因表达降低,血管脂质沉积和AS以及血管CD68表达显著升高;与JWHF组比,WBHF组TG、LDL-C、HOMA-IR、糖耐量曲线下面积(U_GLU)、MDA含量、脂肪直径大小、肝SOD1基因表达、AS病变程度及血管CD68表达上有明显差异。结论高脂高糖饮食能诱导兔形成IR-AS,表现出脂代谢紊乱、炎症和AS病变。但WHBE兔的病变程度明显严重于JW兔,这可能与这两种品系兔在脂质代谢和氧化应激反应存在差异有关。
Objective To explore the phenotypic differences and pathological mechanisms of insulin resistance and atherosclerosis( IR-AS) in white hair black eye( WHBE) rabbits and Japanese white( JW) rabbits. Methods Twelve JW rabbits and 12 WHBE rabbits were randomly divided into the normal control group( NC) and high fat and sugar diet( HF) group with six rabbits in each group. The IR-AS model was induced by feeding a high fat and sugar diet for 12 weeks. At the end of modeling,blood samples were collected to determine blood lipid,superoxide dismutase( SOD),and malondialdehyde( MDA) levels. A glucose tolerance test was conducted,and the area under the curves of blood glucose and insulin was calculated. mRNA expression of microsomal triglyceride transfer protein( MTTP),nuclear factor-like 2( Nrf2),and SOD1 genes in the liver was detected,pathological changes in fat tissues and aortic wall by HE staining,and CD68 expression in aortic tissues were observed. Results Compared with the NC group,HF rabbits showed significant obesity,hyperlipidemia,glucose intolerance,hyperinsulinemia,and increased HOMA-IR. Moreover,HF rabbits exhibited decreased SOD activity and increased MDA contents in their plasma and liver,increased mRNA expression of MTTP and Nrf2 in the liver tissue,and decreased mRNA expression of SOD1. In addition,vascular lipid deposition,AS plaque size,and CD68 expression were increased significantly. Compared with the JWHF group,TG,LDL-C,HOMA-IR,U_GLU,MDA content,fat diameter,SOD1,AS lesion degree,and vascular CD68 expression in the WBHF group were significantly different. Conclusions A high-fat and sugar diet induces the formation of IR-AS in rabbits,resultsing in an obvious lipid metabolism impairment,inflammatory and AS lesions. However,the degree of pathological changes in WHBE rabbits is significantly more serious than that in JW rabbits,which may be related to the differences in lipid metabolism and the oxidative stress response between the two rabbit strains.
Objective To explore the phenotypic differences and pathological mechanisms of insulin resistance and atherosclerosis( IR-AS) in white hair black eye( WHBE) rabbits and Japanese white( JW) rabbits. Methods Twelve JW rabbits and 12 WHBE rabbits were randomly divided into the normal control group( NC) and high fat and sugar diet( HF) group with six rabbits in each group. The IR-AS model was induced by feeding a high fat and sugar diet for 12 weeks. At the end of modeling,blood samples were collected to determine blood lipid,superoxide dismutase( SOD),and malondialdehyde( MDA) levels. A glucose tolerance test was conducted,and the area under the curves of blood glucose and insulin was calculated. mRNA expression of microsomal triglyceride transfer protein( MTTP),nuclear factor-like 2( Nrf2),and SOD1 genes in the liver was detected,pathological changes in fat tissues and aortic wall by HE staining,and CD68 expression in aortic tissues were observed. Results Compared with the NC group,HF rabbits showed significant obesity,hyperlipidemia,glucose intolerance,hyperinsulinemia,and increased HOMA-IR. Moreover,HF rabbits exhibited decreased SOD activity and increased MDA contents in their plasma and liver,increased mRNA expression of MTTP and Nrf2 in the liver tissue,and decreased mRNA expression of SOD1. In addition,vascular lipid deposition,AS plaque size,and CD68 expression were increased significantly. Compared with the JWHF group,TG,LDL-C,HOMA-IR,U_GLU,MDA content,fat diameter,SOD1,AS lesion degree,and vascular CD68 expression in the WBHF group were significantly different. Conclusions A high-fat and sugar diet induces the formation of IR-AS in rabbits,resultsing in an obvious lipid metabolism impairment,inflammatory and AS lesions. However,the degree of pathological changes in WHBE rabbits is significantly more serious than that in JW rabbits,which may be related to the differences in lipid metabolism and the oxidative stress response between the two rabbit strains.
引文
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[17] Bers DM. Cardiac Na/Ca exchange function in rabbit,mouse and man:what’s the difference?[J]. J Mol Cell Cardiol,2002,34(4):369-373.
[18] Wang D,Chen Y,Chabrashvili T,et al. Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin II of afferent arterioles from rabbits infused with angiotensin II[J]. J Am Soc Nephrol,2003,14(11):2783-2789.
[19]周泽华,杨刚毅,李伶,等. JAZF1基因过表达对ApoE~(-/-)小鼠脂代谢及动脉粥样硬化的影响[J].中国糖尿病杂志,2014,22(4):371-376.Zhou ZH,Yang GY,Li L,et al. The effects of JAZF1 gene overexpression on lipids metabolism and atherosclerosis in ApoE-/-mice[J]. Chin J Diabetes,2014,22(4):371-376.
[2] Tran LT,Yuen VG,Mc Neill JH. The fructose-fed rat:a review on the mechanisms of fructose-induced insulin resistance and hypertension[J]. Mol Cell Biochem,2009,332(1-2):145-159.
[3] Hartvigsen K,Binder CJ,Hansen LF,et al. A diet-induced hypercholesterolemic murine model to study atherogenesis without obesity and metabolic syndrome[J]. Arterioscler Thromb Vasc Biol,2007,27(4):878-885.
[4] Saito T,Toriniwa Y,Ishii Y,et al. Hepatic lesions induced by feeding Western diets to Zucker fatty rats,an insulin-resistant model[J]. J Toxicol Pathol,2018,31(4):283-291.
[5] Decock S, Verslype C, Fevery J. Hepatitis C and insulin resistance:mutual interactions[J]. Acta Clin Belg,2007,62(2):111-119.
[6] Sriram N,Kalayarasan S,Sudhandiran G. Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling[J]. Pulm Pharmacol Ther,2009,22(3):221-236.
[7] Jin W,Wang H,Yan W,et al. Role of Nrf2 in protection against traumatic brain injury in mice[J]. J Neurotrauma,2009,26(1):131-139.
[8] Prudencio M,Durazo A,Whitelegge JP,et al. An examination of wild-type SOD1 in modulating the toxicity and aggregation of ALS-associated mutant SOD1[J]. Hum Mol Genet,2010,19(24):4774-4789.
[9]吕朵,朱益民. BRAP基因与心脑血管疾病和代谢综合征研究进展[J].浙江大学学报(医学版),2014,43(5):602-604.Lyu D, Zhu YM. Progress in the effects of BRAP gene on cardiovascular diseases[J]. J Zhejiang Univ(Med Sci),2014,43(5):602-604.
[10]应华忠,寿旗扬,陈民利,等. WHBE兔的血液学指标测定与比较[J].实验动物与比较医学,2010,3(1):44-47.Ying HZ, Shou QY, Chen ML, et al. Determination and comparison of hematological indexes in WHBE rabbits[J]. Lab Anim Comp Med,2010,3(1):44-47.
[11] Waqar AB,Koike T,Yu Y,et al. High-fat diet without excess calories induces metabolic disorders and enhances atherosclerosis in rabbits[J]. Atherosclerosis,2010,213(1):148-155.
[12] Sud N, Zhang H, Pan K, et al. Aberrant expression of microRNA induced by high fructose diet:Implications in the pathogenesis of hyperlipidemia and hepatic insulin resistance[J]. J Nutr Biochem,2017,43:125-131.
[13] Kahn R,Buse J,Ferrannini E,et al. The metabolic syndrome:time for a critical appraisal:joint statement from the American Diabetes Association and the European Association for the Study of Diabetes[J]. Diabetes Care,2005,28(9):2289-2304.
[14]徐永红,贾晓民,赵杰,等.间歇低氧的大鼠模型体内的氧化应激、炎症反应导致代谢紊乱发生的机制[J].中国实用医药,2013,8(29):6-8.Xu YH,Jia XM,Zhao J,et al. Oxidative stress and inflammation resulting in metabolic syndrome in rats dunng chronic intermittent hypoxia[J]. Chin Prac Med,2013,8(29):6-8.
[15]季文静,张翠平,魏文挺,等.蜂王浆酶解产物对D-半乳糖模型小鼠体内抗衰老的作用[J].中国食品学报,2016,16(1):18-25.Ji WJ,Zhang CP,Wei WT,et al. The in vivo antiaging effect of enzymatic hydrolysate from royal jelly in D-galactose induced aging mouse[J]. J Chin Inst Food Sci Technol,2016,16(1):18-25.
[16]潘永明,张利棕,陈民利,等. WHBE兔脾虚型肠易激综合征模型的建立[J].实验动物与比较医学,2008,28(5):313-317.Pan YM,Zhang LZ,Chen ML,et al. Study on irritable bowel syndrome model of spleen deficiency type in WHBE rabbits[J].Lab Anim Comp Med,2008,28(5):313-317.
[17] Bers DM. Cardiac Na/Ca exchange function in rabbit,mouse and man:what’s the difference?[J]. J Mol Cell Cardiol,2002,34(4):369-373.
[18] Wang D,Chen Y,Chabrashvili T,et al. Role of oxidative stress in endothelial dysfunction and enhanced responses to angiotensin II of afferent arterioles from rabbits infused with angiotensin II[J]. J Am Soc Nephrol,2003,14(11):2783-2789.
[19]周泽华,杨刚毅,李伶,等. JAZF1基因过表达对ApoE~(-/-)小鼠脂代谢及动脉粥样硬化的影响[J].中国糖尿病杂志,2014,22(4):371-376.Zhou ZH,Yang GY,Li L,et al. The effects of JAZF1 gene overexpression on lipids metabolism and atherosclerosis in ApoE-/-mice[J]. Chin J Diabetes,2014,22(4):371-376.