通过RNA测序和生物信息分析在载脂蛋白E基因敲除小鼠中鉴定与动脉粥样硬化合并症和抑郁行为相关的基因和通路
Identification of genes and pathways related to atherosclerosis comorbidity and depressive behavior via RNA-seq and bioinformation analysis in ApoE mice.
作者信息
Zhou Junjie, Zhang Chunjie, Wu Xiaoyun, Xie Qi, Li Lan, Chen Ying, Yan Hongbin, Ren Ping, Huang Xi
机构信息
Institute of TCM-related Comorbid Depression, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Medical College, Xiamen University, Xiamen 361102, China.
出版信息
Ann Transl Med. 2019 Dec;7(23):733. doi: 10.21037/atm.2019.11.118.
BACKGROUND
Depression is an independent risk factor for atherosclerosis (AS), which can increase the risk of death and disability from AS. However, the mechanism of AS comorbidity with depression is complex.
METHODS
ApoE and C57BL/6J mice were fed with a high-fat diet (model group, N=12 ♂) and a normal diet (control group, N=12 ♂). During the 15-week experimental period, the following tests were performed: coat color score, body weight, and sucrose preference tests (every 2 weeks); open-field test (1, 7, and 15 weeks); and light/dark and tail suspension tests (15 week). Oil Red O and hematoxylin and eosin (HE) stainings were used to assess the area of atherosclerotic status. The levels of triglyceride and total and low-density lipoprotein cholesterol in the serum and secretion of pro-inflammatory cytokines were determined using the enzyme-linked immunosorbent assay. The differentially expressed genes (DEGs) in the hippocampus and prefrontal cortex were screened by RNA-sequencing (RNA-seq) and analyzed using the Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations.
RESULTS
Our findings showed that compared with C57 mice in the control group, ApoE mice in the model group gradually developed depression-like behavioral changes with elevated blood lipid concentrations, serum inflammatory factor levels, and atherosclerotic plaque formation in the thoracic aorta. Consequently, in the RNA-seq and bioinformatics analysis, the high expression of inflammatory chemokine genes was found in the hippocampus and prefrontal cortex area. The regulation of movement, feeding, and reproduction of the gene expression decreased.
CONCLUSIONS
These results indicate that when ApoE mice were fed a high-fat diet for 15 weeks, depression-like behavioral changes occurred with the formation of atherosclerotic lesions. The RNA-seq, combined with bioinformatics analysis, showed that this AS comorbidity with depressive behavior was associated with the high expression of inflammation-related genes and pathways in the hippocampus and prefrontal cortex.
背景
抑郁症是动脉粥样硬化（AS）的独立危险因素，可增加AS导致的死亡和残疾风险。然而，AS合并抑郁症的机制复杂。
方法
将载脂蛋白E（ApoE）小鼠和C57BL/6J小鼠分别给予高脂饮食（模型组，N = 12只雄性）和正常饮食（对照组，N = 12只雄性）。在15周的实验期内，进行以下测试：毛色评分、体重和蔗糖偏好测试（每2周进行一次）；旷场试验（第1、7和15周）；明暗箱试验和悬尾试验（第15周）。采用油红O染色和苏木精-伊红（HE）染色评估动脉粥样硬化状态面积。使用酶联免疫吸附测定法测定血清中甘油三酯、总胆固醇和低密度脂蛋白胆固醇水平以及促炎细胞因子的分泌。通过RNA测序（RNA-seq）筛选海马体和前额叶皮质中的差异表达基因（DEG），并使用基因本体（GO）注释和京都基因与基因组百科全书（KEGG）注释进行分析。
结果
我们的研究结果表明，与对照组中的C57小鼠相比，模型组中的ApoE小鼠逐渐出现类似抑郁的行为变化，同时血脂浓度、血清炎症因子水平升高，胸主动脉出现动脉粥样硬化斑块形成。因此，在RNA-seq和生物信息学分析中，发现海马体和前额叶皮质区域炎症趋化因子基因高表达。基因表达的运动、进食和繁殖调节功能下降。
结论
这些结果表明，当ApoE小鼠给予高脂饮食15周时，会出现类似抑郁的行为变化并伴有动脉粥样硬化病变形成。RNA-seq结合生物信息学分析表明，这种AS合并抑郁行为与海马体和前额叶皮质中炎症相关基因和通路的高表达有关。
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