rAAV2/1-Acrp30对动脉粥样硬化的GK大鼠血脂及NF-κB的影响
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摘要
目的:观察rAAV2/1-Acrp30对动脉粥样硬化GK大鼠模型血脂,血清可溶性细胞间黏附分子(sICAM-1)水平及主动脉处NF-κBp65mRNA表达的影响,从血管炎症及脂质代谢的角度探讨脂联素对糖尿病大血管病变的作用。
材料和方法:将GK大鼠随机分为模型组及对照组,以高脂饲料联合一氧化氮合酶抑制剂L-N-硝基精氨酸甲酯(L-NAME)灌胃建立动脉粥样硬化GK大鼠模型。造模8周后处死部分大鼠进行主动脉病理学检查以鉴定造模是否成功。随后将造模成功的30只动脉粥样硬化的GK大鼠分为3个处理组:①模型1组:后肢肌肉注射盐水;②模型2组:后肢肌肉注射空病毒rAAV2/1;③治疗组:后肢肌肉注射rAAV2/1-Acrp30:1×10~(12)v.g/ml。治疗8周后处死所有大鼠,比较三组之间血脂、血清sICAM-1及主动脉处NF-κBp65mRNA的表达水平的不同。
结果:
1.造模8周后,模型组大鼠可见大量泡沫细胞形成,内皮细胞不连续,内皮细胞肿胀等动脉粥样硬化特征性病理改变。
2.治疗组和模型1组、模型2组比较,血清TG、TC、LDL-C水平显著降低(p均＜0.05),HDL-C水平显著升高(p＜0.05)。
3.治疗组和模型1组、模型2组比较,血清sICAM-1显著降低(p＜0.05)。
4.治疗组和模型1组、模型2组比较,主动脉NF-κBp65mRNA表达显著下调(p＜0.05)。
结论:
1.通过高脂饲料联合L-NAME灌胃可成功建立动脉粥样硬化GK大鼠模型,可用作研究2型糖尿病大血管病变。
2.rAAV2/1-Acrp30可通过调节血脂代谢,抑制NF-κB的表达,减轻炎症反应而对糖尿病大血管病变产生保护作用。
OBJECTIVE: To explore the effects of adiponectin on diabetic macroangiopathy, we observed the changes of serum lipids, serum soluble intercellular adhesion molecular (sICAM-1) levels and nuclear factor-κBp65 (NF-κBp65) expressions in aorta after transferring rAAV2/1-Acrp30 to atherosclerotic GK rats.
METHODS : We set up type 2 diabetic atherosclerotic rat models by feeding GK rats with high-fat diet and L-N-arginine-methylesten intragastric administration. A total number of 30 atherosclerotic GK rat models were randomly divided into three groups:①Model group one (M1): hind limb intramuscular injection of normal saline;②Model group two(M2): hind limb intramuscular injection of vacuity virus rAAV2/1 ;③Treatment group(T): hind limb intramuscular injection of rAAV2/1-Acrp30 with a dose of 1×10~(12) v.g/ml. After 8 weeks, we measured serum lipids, sICAM-1 levels and aortic NF-κBp65mRNA expressions in each group. Aortic NF-κBp65mRNA expression was measured by RT-PCR.
RESULTS:
1. After 8 weeks of high-fat diet plus L-NAME intragastric administration, characteristics changes of atherosclerosis were observed in aortas of model rats, such as massive foam cells, swell and discontinuous endothelial cells.
2. Compared with control model groups (M1 and M2), levels of TG、TC、LDL-C in treatment (T) group were decreased significantly (p <0.05) , while levels of HDL-C increased significantly in group T (p <0.05).
3. Compared with control model groups (M1 and M2) , sICAM-1 levels in treatment (T) group were decreased significantly (P<0.05) .
4.Compared with control model groups (M1 and M2) , aortic NF-κBp65 mRNA expressions were significantly down-regulated in the treatment (T) group (P<0.05) .
CONCLUSIONS:
1. Rat models with diabetic atherosclerosis can be established by feeding GK rats with high-fat diet and L-N-arginine-methylesten intragastric administration.
2. rAAV2/1-Acrp30 may produce protective effects on diabetic atherosclerosis by modulating lipids metabolism and decreasing inflammatory reactions.
材料和方法:将GK大鼠随机分为模型组及对照组,以高脂饲料联合一氧化氮合酶抑制剂L-N-硝基精氨酸甲酯(L-NAME)灌胃建立动脉粥样硬化GK大鼠模型。造模8周后处死部分大鼠进行主动脉病理学检查以鉴定造模是否成功。随后将造模成功的30只动脉粥样硬化的GK大鼠分为3个处理组:①模型1组:后肢肌肉注射盐水;②模型2组:后肢肌肉注射空病毒rAAV2/1;③治疗组:后肢肌肉注射rAAV2/1-Acrp30:1×10~(12)v.g/ml。治疗8周后处死所有大鼠,比较三组之间血脂、血清sICAM-1及主动脉处NF-κBp65mRNA的表达水平的不同。
结果:
1.造模8周后,模型组大鼠可见大量泡沫细胞形成,内皮细胞不连续,内皮细胞肿胀等动脉粥样硬化特征性病理改变。
2.治疗组和模型1组、模型2组比较,血清TG、TC、LDL-C水平显著降低(p均＜0.05),HDL-C水平显著升高(p＜0.05)。
3.治疗组和模型1组、模型2组比较,血清sICAM-1显著降低(p＜0.05)。
4.治疗组和模型1组、模型2组比较,主动脉NF-κBp65mRNA表达显著下调(p＜0.05)。
结论:
1.通过高脂饲料联合L-NAME灌胃可成功建立动脉粥样硬化GK大鼠模型,可用作研究2型糖尿病大血管病变。
2.rAAV2/1-Acrp30可通过调节血脂代谢,抑制NF-κB的表达,减轻炎症反应而对糖尿病大血管病变产生保护作用。
OBJECTIVE: To explore the effects of adiponectin on diabetic macroangiopathy, we observed the changes of serum lipids, serum soluble intercellular adhesion molecular (sICAM-1) levels and nuclear factor-κBp65 (NF-κBp65) expressions in aorta after transferring rAAV2/1-Acrp30 to atherosclerotic GK rats.
METHODS : We set up type 2 diabetic atherosclerotic rat models by feeding GK rats with high-fat diet and L-N-arginine-methylesten intragastric administration. A total number of 30 atherosclerotic GK rat models were randomly divided into three groups:①Model group one (M1): hind limb intramuscular injection of normal saline;②Model group two(M2): hind limb intramuscular injection of vacuity virus rAAV2/1 ;③Treatment group(T): hind limb intramuscular injection of rAAV2/1-Acrp30 with a dose of 1×10~(12) v.g/ml. After 8 weeks, we measured serum lipids, sICAM-1 levels and aortic NF-κBp65mRNA expressions in each group. Aortic NF-κBp65mRNA expression was measured by RT-PCR.
RESULTS:
1. After 8 weeks of high-fat diet plus L-NAME intragastric administration, characteristics changes of atherosclerosis were observed in aortas of model rats, such as massive foam cells, swell and discontinuous endothelial cells.
2. Compared with control model groups (M1 and M2), levels of TG、TC、LDL-C in treatment (T) group were decreased significantly (p <0.05) , while levels of HDL-C increased significantly in group T (p <0.05).
3. Compared with control model groups (M1 and M2) , sICAM-1 levels in treatment (T) group were decreased significantly (P<0.05) .
4.Compared with control model groups (M1 and M2) , aortic NF-κBp65 mRNA expressions were significantly down-regulated in the treatment (T) group (P<0.05) .
CONCLUSIONS:
1. Rat models with diabetic atherosclerosis can be established by feeding GK rats with high-fat diet and L-N-arginine-methylesten intragastric administration.
2. rAAV2/1-Acrp30 may produce protective effects on diabetic atherosclerosis by modulating lipids metabolism and decreasing inflammatory reactions.
引文
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[10]于运福等,动脉粥样硬化中的核转录因子,实用诊断与治疗杂志2006年第20卷第4期,277-278
[11]程津新,毛用敏等,的分子生物学活性及其在疾病中的作用,天津医药,2004年3月第32卷第3期,189-191
[12]OuchiN,KiharaS,Arita Y,etal.Adiponection,an adipocyte-derived plasma protein inhibits endothelial NF-kappaB signaling through cAMP-dependent pathway.Circulation,2000,102:1296-1301
[13]OuchiN,KiharaS,AritaY,etal.Adipocyte-derived plasma protein,adiponectin,suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived acrophages.Circulation,2001,103:1057-1063.
[14]王芬,何华亮等,自发的2型糖尿病动物模型,中国实验动物学报October,2007 Vol.15 No395-398
[15]GerrityRG,NatarajanR,NadlerJL,etal.Diabetes2 induced accelerated atherosclerosis in Swine[J].Diabetes,2001,50(7):1654-1665.
[16]RenardCB,KramerF,JohanssonF,etal.Diabetes and diabetes associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions[J].J ClinInvest,2004,114(5):659-668.
[17]GrundySM,HowardB,SmithJrS,et al.Prevention conference Ⅵ:diabetes and cardiovascular disease:executive summary:conference proceding for healthcare professionals from aspecial writing group of the American Heart Association [J].Circulation,2002,105(18):2231-2239.
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