Reduced vascular responsiveness to adiponectin in hyperlipidemic rats-mechanisms and significance
Reduced vascular responsiveness to adiponectin in hyperlipidemic rats-mechanisms and significance
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DOI：
10.1016/j.yjmcc.2010.03.002
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发表时间：
2010-09-01
影响因子：
5
通讯作者：
Ma, Xin-Liang
中科院分区：
文献类型：
--
作者：
Li, Rong;Xu, Ming;Ma, Xin-Liang
脂联素（APN）是一种脂肪细胞来源的血管保护分子，其缺乏可导致糖尿病血管损伤。本研究旨在探讨肥胖/高脂血症是否会改变APN的血管反应性，并探讨其相关机制和病理意义。成年雄性Sprague-Dawley大鼠喂食常规或高脂肪饮食（HF）4-16周。测定循环APN水平、主动脉pAMPK/AMPK、peNOS/eNOS和APN受体表达水平。与喂食对照饮食的时间匹配的动物相比，HF饮食动物的血浆APN水平在8周时显著升高，此后迅速下降。尽管循环APN水平不变或升高，但血管组织中磷酸化AMPK和eNOS在所有观察时间点均显著降低。重组全长APN（rAPN）诱导的AMPK/eNOS磷酸化和血管舒张在16周的肥胖/高血压主动脉节段显着减少。HF饮食后16周，血管APN受体1（AdipoR 1）和受体2（AdipoR 2）表达显著降低。rAPN与肥胖/高血压血浆预孵育，而不是与正常血浆，显著降低其AMPK和eNOS激活作用，并减弱其对TNF α诱导的HUVEC凋亡的保护作用。这项研究首次证明了肥胖/高脂血症降低了血管对APN的反应性。在肥胖/高脂血症血浆中存在的未鉴定因子对APN的修饰/失活、降低的血管AdipoR 1/R2表达和降低的循环APN水平有助于在肥胖状况的不同阶段降低血管对APN的反应性。APN生物活性降低使得TNF α促凋亡和促炎作用未减轻，从而导致肥胖/高脂血症中的血管损伤。(C)2010爱思唯尔有限公司保留所有权利。
Deficiency of adiponectin (APN), an adipocyte-derived vascular protective molecule, contributes to diabetic vascular injury. The current study determined whether obesity/hyperlipidemia may alter the vascular response to APN, and investigated the involved mechanisms and pathologic significance. Adult male Sprague-Dawley rats were fed a regular or high-fat diet (HF) for 4-16 weeks. Circulating APN levels, aortic pAMPK/AMPK, peNOS/eNOS, and APN receptor expression levels were determined. Compared to time-matched animals fed control diet, plasma APN levels in HF-diet animals were significantly increased at 8 weeks, and rapidly declined thereafter. Despite unchanged or elevated circulating APN levels, phosphorylated AMPK and eNOS in vascular tissue were significantly reduced at all observed time points. Recombinant full-length APN (rAPN)-induced AMPK/eNOS phosphorylation and vasodilatation were significantly reduced in 16-week obese/hyperlipidemic aortic segments. Vascular APN receptor 1 (AdipoR1) and receptor 2 (AdipoR2) expression were significantly reduced 16 weeks after HF-diet. Pre-incubation of rAPN with obese/hyperlipidemic plasma, but not with normal plasma, significantly reduced its AMPK and eNOS activation effect, and blunted its protective effect against TNF alpha-induced HUVEC apoptosis. This study demonstrated for the first time that obesity/hyperlipidemia reduces vascular responsiveness to APN. Modification/inactivation of APN by unidentified factors present in obese/hyperlipidemic plasma, decreased vascular AdipoR1/R2 expression, and reduced circulating APN levels contribute to reduced vascular responsiveness to APN at different stages of the obese condition. Reduced APN bioactivity allows unmitigated TNF alpha pro-apoptotic and pro-inflammatory actions, contributing to vascular injury in obesity/hyperlipidemia. (C) 2010 Elsevier Ltd. All rights reserved.