«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:

2011年第4期

页码:

450

栏目:

基础研究

出版日期:

2011-08-25

文章信息/Info

Title:

Mechanisms of vascular adiponectin resistance in hypercholesterolemic rats

作者:

王文清¹; 张荣怀²; 王晓明²; 李榕²

第四军医大学：1.西京医院血液科，2.西京医院老年病科，陕西 西安 710032

Author(s):

WANG Wen-qing¹;  ZHANG Rong-huai²;  WANG Xiao-ming²;  LI Rong²

1.Department of Hematology, Xijing Hospital, 2.Department of Geriatrics, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China

关键词:

脂联素抵抗; 高胆固醇血症; 血管; 大鼠

Keywords:

adiponectin;  hypercholesterolemia;  vasculature;  rat;  mechanisms

分类号:

Q548.1　

DOI:

61-1268/R.20110503.1425.008

文献标识码:

A

摘要:

目的:观察高胆固醇血症大鼠血管对脂联素(adiponectin,APN)的反应是否发生改变，并探讨其相关机制。方法： 将50只雄性SD大鼠随机分为10组，每组5只，分别以正常及高胆固醇饲料喂养0周、4周、8周、12周及16周。喂养结束后，麻醉采血检测血浆中胆固醇和APN的水平。分离大鼠主动脉，检测血管组织中腺苷酸活化的蛋白激酶(AMPK)的磷酸化（p-AMPK）和APN受体（adipoR1）表达的水平。将其血管组织与重组人APN（rAPN）共孵育，再次观察rAPN对血管组织中p-AMPK的影响。将大鼠血浆与rAPN共孵育4 h，观察孵育后的rAPN对人脐静脉血内皮细胞（HUVEC）p-AMPK的影响。结果： 与喂养时间相同的正常饲料喂养组相比，以高脂饲料喂养8周、12周及16周后，血浆胆固醇的含量显著升高（8周：P<0.05；12周及16周：P<0.01）。与喂养时间相同的正常饲料喂养组比较，高脂饲料喂养8周时，血浆APN的水平显著升高（P<0.05），随后呈降低趋势，喂养16周时低于正常值。与喂养时间相同的正常饲料喂养组比较，rAPN 激活的AMPK的水平在高脂饲料喂养12周后显著降低，且AdipoR1表达的水平在以高脂饲料喂养16周组中显著降低（P<0.05）。以高胆固醇血症大鼠血浆孵育的rAPN与以正常大鼠血浆孵育的rAPN相比，前者刺激HUVECs中AMPK磷酸化的水平显著降低（P<0.01）。结论： 高胆固醇血症大鼠存在血管APN抵抗，早期与高脂血浆中存在某种物质抑制APN的活性有关，晚期还与APN的含量及AdipoR1水平的降低有关。

Abstract:

AIM:To observe vascular responsiveness to adiponectin in hypercholesterolemic rats and to investigate the mechanisms involved. METHODS: Fifty male Sprague Dawley (SD) rats were randomized to receive a regular rat chow diet or a high-fat diet for 0-16 weeks, and circulating cholesterol and adiponectin levels were determined. The aortas of rats were isolated and the expression of AMPK phosphoralytion (p-AMPK) and adiponectin receptor (AdipoR1) was detected. Aortas were incubated with recombinant full-length adiponectin (rAPN) and rAPN-induced AMPK phosphorylation was observed. rAPN was incubated with rat plasma for 4 h and then the effect of treated rAPN on AMPK phosphorylation in human umbilical vein endothelial cells was observed. RESULTS: Compared with that in rats fed with regular diet, cholesterol concentration increased after 8 weeks of the high-fat diet. Adiponectin levels in animals fed a high-fat diet significantly increased at 8 weeks and rapidly declined thereafter. The expression of rAPN-induced p-AMPK and AdipoR1 was reduced in rats fed a high-fat diet. Pre-incubation of rAPN with high-fat plasma rather than normal plasma significantly decreased the AMPK activation effect. CONCLUSION: The present study demonstrates that hypercholesterolemia causes vascular adiponectin resistance. Adiponectin modification/inactivation by unidentified factors in hypercholesterolemic plasma is likely responsible for early phase adiponectin resistance. A combination of adiponectin modification/inactivation reduced circulating adiponectin and decreased AdipoR1 expression and is responsible for late phase adiponectin resistance.

参考文献/References

[1]Ouchi N,Shibata R,Walsh K.Cardioprotection by adiponectin
Trends Cardiovasc Med,2006,16(5): 141-146.
[2]Li R,Wang WQ,Zhang H,et al.Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity[J].Am J Physiol Endocrinol Metab,2007,293(6):E1703-E1708
[3]李榕,王文清,张海锋，等.ANT对高脂大鼠内皮功能的影响及其分子机制[J].心脏杂志,2010,22(3):318-321,331.
[4]Zhou L, Deepa SS,Etzler JC,et al.Adiponectin activates AMPactivated protein kinase in muscle cells via APPL1/LKB1-dependent and phospholipase C/Ca2+/Ca2+/calmodulin-dependent protein kinase kinasedependent pathways[J].J Biol Chem,2009,284(33):22426-22435.
[5]Goldstein BJ,Scalia R.Adiponectin:A novel adipokine linking adipocytes and vascular function[J].J Clin Endocrinol Metab,2004,89(6):2563-2568.
[6]Kumada M,Kihara S,Sumitsuji S,et al.Association of hypoadiponectinemia with coronary artery disease in men[J].Arterioscler Thromb Vasc Biol,2003, 23(1):85-89.
[7]Hotta K,Funahashi T,Arita Y,et al.Plasma concentrations of a novel, adipose-specific protein,adiponectin,in type 2 diabetic patients[J].Arterioscler Thromb Vasc Biol, 2000,20(6):1595-1599.
[8]Semple RK,Halberg NH,Burling K,et al.Paradoxical elevation of high-molecular weight adiponectin in acquired extreme insulin resistance due to insulin receptor antibodies[J].Diabetes,2007,56(6):1712-1717.
[9]Kanety H,Hemi R,Ginsberg S,et al.Total and high molecular weight adiponectin are elevated in patients with Laron syndrome despite marked obesity[J].Eur J Endocrinol,2009,161(6):837-844.
[10]Rodriguez A,Catalan V,Becerril S,et al.Impaired adiponectin-AMPK signalling in insulin-sensitive tissues of hypertensive rats[J]. Life Sci,2008,83(15-16):540-549.
[11]Mullen KL,Smith AC,Junkin KA,et al.Globular adiponectin resistance develops independently of impaired insulin-stimulated glucose transport in soleus muscle from high-fat-fed rats[J].Am J Physiol Endocrinol Metab,2007,293(1):E83-E90.
[12]Lin HV, Kim JY,Pocai A,et al.Adiponectin resistance exacerbates insulin resistance in insulin receptor transgenic/knockout mice[J].Diabetes,2007,56(8):1969-1976.
[13]Bonnard C,Durand A,Vidal H,et al.Changes in adiponectin,its receptors and AMPK activity in tissues of diet-induced diabetic mice[J].Diab Metab,2008,34(1):52-61.
[14]Zhu W,Cheng KK,Vanhoutte PM,et al.Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention[J].Clin Sci (Lond),2008,114(5):361-374.
[15]Goldstein BJ,Scalia RG,Ma XL.Protective vascular and myocardial effects of adiponectin[J].Nat Clin Pract Cardiovasc Med,2009,6(1):27-35.

备注/Memo

备注/Memo:

收稿日期：2010-12-08.基金项目：国家自然科学基金项目资助（30700308） 通讯作者：李榕，主治医师，主要从事代谢综合征发病机制及防治的研究Email:rongli.li09@gmail.com 作者简介：王文清，主治医师，博士Email:scwwq@yahoo.com.cn

常用功能

更新日期/Last Update: 2011-06-02