Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice.
Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice.
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DOI：
10.3389/fphys.2018.00229
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发表时间：
2018
影响因子：
4
通讯作者：
Davel AP
中科院分区：
文献类型：
--
作者：
Baltieri N;Guizoni DM;Victorio JA;Davel AP
背景：内皮功能障碍在动脉粥样硬化的发生中起着关键作用。血管胰岛素抵抗可能导致内皮细胞一氧化氮（NO）生成减少，导致心脏代谢疾病中内皮依赖性舒张功能受损。由于血管周围脂肪组织（PVAT）控制内皮功能和NO的生物利用度，我们假设的作用，这种脂肪存款的血管并发症与动脉粥样硬化的初始阶段。因此，我们研究了PVAT在高胆固醇血症LDL受体敲除小鼠（LDLr-KO）早期内皮功能障碍中的潜在参与。方法：从4月龄的C57 BL/6 J（WT）和LDLr-KO小鼠中分离出有和没有PVAT的胸部肿瘤。研究PVAT对乙酰胆碱、胰岛素和硝普钠舒张反应的贡献。Western blotting检测主动脉PVAT中内皮型一氧化氮合酶（eNOS）和脂联素的表达，以及胰岛素信号通路。结果：与WT小鼠相比，LDLr-KO小鼠的无PVAT主动脉表现出乙酰胆碱和胰岛素诱导的舒张功能受损。在LDLr-KO小鼠中，PVAT的存在恢复了两种血管舒张反应，与乙酰胆碱诱导的NO水平升高相关。PVAT并没有改变血管舒张反应，乙酰胆碱和胰岛素在WT小鼠，而血管舒张诱发的NO供体硝普钠没有修改基因型或PVAT。胰岛素受体底物-1（IRS-1）、磷脂酰肌醇3-激酶（PI 3 K）、AKT、ERK 1/2、AKT（Ser 473）和ERK 1/2（Thr 202/Tyr 204）磷酸化以及脂联素的表达在WT和LDLr-KO小鼠的PVAT中相似，表明PVAT胰岛素信号传导无变化。然而，eNOS表达在LDLr-KO小鼠的PVAT中增强，而eNOS表达在无PVAT的卵巢中不太丰富。结论：这些结果表明，升高eNOS衍生的NO生产主动脉PVAT可能是一种代偿机制的内皮功能障碍和受损的血管扩张作用的胰岛素在高胆固醇血症的LDL受体缺陷小鼠。在缺乏致动脉粥样硬化饮食的遗传性高胆固醇血症中，这种保护作用可能限制动脉粥样硬化的进展。
Background: Endothelial dysfunction plays a pivotal role in the initiation of atherosclerosis. Vascular insulin resistance might contribute to a reduction in endothelial nitric oxide (NO) production, leading to impaired endothelium-dependent relaxation in cardiometabolic diseases. Because perivascular adipose tissue (PVAT) controls endothelial function and NO bioavailability, we hypothesized a role for this fat deposit in the vascular complications associated with the initial stages of atherosclerosis. Therefore, we investigated the potential involvement of PVAT in the early endothelial dysfunction in hypercholesterolemic LDL receptor knockout mice (LDLr-KO). Methods: Thoracic aortas with and without PVAT were isolated from 4-month-old C57BL/6J (WT) and LDLr-KO mice. The contribution of PVAT to relaxation responses to acetylcholine, insulin, and sodium nitroprusside was investigated. Western blotting was used to examine endothelial NO synthase (eNOS) and adiponectin expression, as well the insulin signaling pathway in aortic PVAT. Results: PVAT-free aortas of LDLr-KO mice exhibited impaired acetylcholine- and insulin-induced relaxation compared with those of WT mice. Both vasodilatory responses were restored by the presence of PVAT in LDLr-KO mice, associated with enhanced acetylcholine-induced NO levels. PVAT did not change vasodilatory responses to acetylcholine and insulin in WT mice, while vascular relaxation evoked by the NO donor sodium nitroprusside was not modified by either genotype or PVAT. The expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), AKT, ERK1/2, phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204), and adiponectin was similar in the PVAT of WT and LDLr-KO mice, suggesting no changes in PVAT insulin signaling. However, eNOS expression was enhanced in the PVAT of LDLr-KO mice, while eNOS expression was less abundant in PVAT-free aortas. Conclusion: These results suggest that elevated eNOS-derived NO production in aortic PVAT might be a compensatory mechanism for the endothelial dysfunction and impaired vasodilator action of insulin in hypercholesterolemic LDLr-deficient mice. This protective effect may limit the progression of atherosclerosis in genetic hypercholesterolemia in the absence of an atherogenic diet.
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影响因子：
20.1
作者：
Chatterjee TK;Stoll LL;Denning GM;Harrelson A;Blomkalns AL;Idelman G;Rothenberg FG;Neltner B;Romig-Martin SA;Dickson EW;Rudich S;Weintraub NL
通讯作者：
Weintraub NL
血管周围脂肪组织来源的脂联素通过促进巨噬细胞自噬抑制项圈诱导的颈动脉粥样硬化。
影响因子：
3.7
作者：
Li C;Wang Z;Wang C;Ma Q;Zhao Y
通讯作者：
Zhao Y
影响因子：
9.3
作者：
Franco, Nathalia da Silva;Lubaczeuski, Camila;Davel, Ana P.
通讯作者：
Davel, Ana P.
影响因子：
37.8
作者：
Chang L;Villacorta L;Li R;Hamblin M;Xu W;Dou C;Zhang J;Wu J;Zeng R;Chen YE
通讯作者：
Chen YE
DOI：
10.1161/atvbaha.114.303029
发表时间：
2014-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Brown NK;Zhou Z;Zhang J;Zeng R;Wu J;Eitzman DT;Chen YE;Chang L
通讯作者：
Chang L