Endoplasmic reticulum stress in perivascular adipose tissue promotes destabilization of atherosclerotic plaque by regulating GM-CSF paracrine.
Endoplasmic reticulum stress in perivascular adipose tissue promotes destabilization of atherosclerotic plaque by regulating GM-CSF paracrine.
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血管周围脂肪组织中的内质网应激通过调节 GM-CSF 旁分泌促进动脉粥样硬化斑块的不稳定
DOI：
10.1186/s12967-018-1481-z
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发表时间：
2018-04-18
影响因子：
7.4
通讯作者：
Wang JF
中科院分区：
文献类型：
--
作者：
Ying R;Li SW;Chen JY;Zhang HF;Yang Y;Gu ZJ;Chen YX;Wang JF
背景：血管周围脂肪组织（PVAT）加速斑块进展，增加心血管风险。我们验证了PVAT导致斑块易损性的假设，并研究了PVAT中的内质网应激（ER应激）是否在易损性斑块中起重要作用。方法将供体小鼠的胸主动脉PVAT或皮下脂肪组织作为对照移植到受体载脂蛋白E缺陷（apoE−/−）小鼠的颈动脉中，去除颈动脉项圈后放置6周。移植2周后，局部给药内质网应激抑制剂4-苯基丁酸（4- pba）， 4周后安乐死。采用免疫组化方法量化斑块组成和新生血管。采用小鼠血管生成抗体阵列试剂盒检测移植脂肪组织产生的血管生成因子。采用体外成管法、划痕迁移法和小鼠主动脉环法评价移植PVAT上清的血管生成能力。结果透射电镜超微结构检测显示，移植的PVAT为白色和棕色混合脂肪细胞群，线粒体丰富。移植后的PVAT增加斑块内巨噬细胞浸润、脂质核心、内膜和血管血管新生以及斑块中MMP2/9的表达，减少动脉粥样硬化斑块中平滑肌细胞和胶原的表达，局部4- pba处理后斑块恢复。抗体阵列分析显示，4-PBA降低了PVAT分泌的几种血管生成因子[粒细胞巨噬细胞集落刺激因子（GM-CSF）， MCP-1, IL-6]。此外，与移植的PVAT条件培养基相比，4-PBA处理的PVAT条件培养基抑制了内皮细胞的管形成、迁移能力和离体小鼠主动脉环血管生成。ER应激下脂肪细胞中GM-CSF mRNA表达和蛋白水平均显著升高，并受4-PBA的抑制。此外，染色质免疫沉淀分析证实，内质网应激增强了脂肪细胞中NF-κB与小鼠GM-CSF基因启动子的结合。结论研究结果表明，内质网应激在一定程度上通过转录因子NF-κB增加GM-CSF旁分泌来破坏动脉粥样硬化斑块的稳定。
BackgroundPerivascular adipose tissue (PVAT) accelerates plaque progression and increases cardiovascular risk. We tested the hypothesis that PVAT contributed to plaque vulnerability and investigated whether endoplasmic reticulum stress (ER stress) in PVAT played an important role in vulnerable plaque.MethodsWe transplanted thoracic aortic PVAT or subcutaneous adipose tissue as a control, from donor mice to carotid arteries of recipient apolipoprotein E deficient (apoE−/−) mice after removing carotid artery collar placed for 6 weeks. Two weeks after transplantation, ER stress inhibitor 4-phenyl butyric acid (4-PBA) was locally administrated to the transplanted PVAT and then animals were euthanized after 4 weeks. Immunohistochemistry was performed to quantify plaque composition and neovascularization. Mouse angiogenesis antibody array kit was used to test the angiogenic factors produced by transplanted adipose tissue. In vitro tube formation assay, scratch wound migration assay and mouse aortic ring assay were used to assess the angiogenic capacity of supernatant of transplanted PVAT.ResultsUltrastructural detection by transmission electron microscopy showed transplanted PVAT was a mixed population of white and brown adipocytes with abundant mitochondria. Transplanted PVAT increased the intraplaque macrophage infiltration, lipid core, intimal and vasa vasorum neovascularization and MMP2/9 expression in plaque while decreased smooth muscle cells and collagen in atherosclerotic plaque, which were restored by local 4-PBA-treatment. Antibody array analysis showed that 4-PBA reduced several angiogenic factors [Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), MCP-1, IL-6] secreted by PVAT. Besides, conditioned medium from 4-PBA treated-PVAT inhibited tube formation and migration capacity of endothelial cells and ex vivo mouse aortic ring angiogenesis compared to conditioned medium from transplanted PVAT. mRNA expression and protein levels of GM-CSF were markedly elevated in adipocytes under ER stress which would be suppressed by 4-PBA. In addition, ER stress enhanced NF-κB binding to the promoter of the mouse GM-CSF gene in adipocytes confirmed by Chromatin immunoprecipitation analyses.ConclusionsOur findings demonstrate that ER stress in PVAT destabilizes atherosclerotic plaque, in part through increasing GM-CSF paracrine via transcription factor NF-κB.
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DOI：
10.1161/atvbaha.114.303983
发表时间：
2014-08
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Manka D;Chatterjee TK;Stoll LL;Basford JE;Konaniah ES;Srinivasan R;Bogdanov VY;Tang Y;Blomkalns AL;Hui DY;Weintraub NL
通讯作者：
Weintraub NL
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
影响因子：
37.8
作者：
Haghighat, Amir;Weiss, Daiana;Taylor, W. Robert
通讯作者：
Taylor, W. Robert
影响因子：
3.2
作者：
Jonkman, James E. N.;Cathcart, Judith A.;Colarusso, Pina
通讯作者：
Colarusso, Pina
影响因子：
1.6
作者：
Dong, Dan-Dan;Wang, Kai;Shen, Bao-Zhong
通讯作者：
Shen, Bao-Zhong