基于抑郁模型代谢组学探索抑郁对心血管系统的影响

发布时间：2018-06-17 09:37

本文选题：强迫游泳 + 抑郁症　；参考：《中南大学》2013年博士论文

【摘要】：抑郁症会使心血管疾病的发病率升高,其机制的研究仍处于探索之中。慢性轻度不可预见性应激(CUMS)模型是一种广泛使用的抑郁症模型,在这里我们采用一个GC/MS为基础的代谢轮廓分析方法,探索抑郁模型大鼠心肌代谢轮廓的变化。利用主成分分析(PCA)和偏最小二乘判别分析(PLS-DA)来揭示抑郁模型和对照组之间的差异。结果发现具有心脏保护作用的分子—谷氨酰胺(P=0.019)和肌苷(P=0.013),作为心脏主要能源的分子—脂肪酸(9,12-十八碳二烯酸,p=0.002；棕榈酸,P=0.006；硬脂酸,P=0.030)和合成心肌胶原分子的前体—脯氨酸(P=0.036)在抑郁模型组中下调。根据心肌代谢组学结果并结合文献,我们推测糖脂代谢、调节糖脂代谢的脂联素以及乙醛脱氢酶2(ALDH2)可能在抑郁心血管疾病共病中发挥作用。采用CUMS抑郁模型,观测其体内糖脂代谢、乙醛脱氢酶2和脂联素水平的变化。此外研究了舍曲林对上述指标的影响。CUMS模型组大鼠糖水偏好量和海马脑源性神经营养因子(BDNF)明显降低,说明抑郁模型成功建立。CUMS降低了血清脂联素、高密度脂蛋白胆固醇(HDL-C)、总胆固醇(TC)、甘油三酯(TG)、游离脂肪酸(FFA)的水平。舍曲林治疗后显著恢复了血清脂联素、HDL-C的水平。在海马中发现脂联素mRNA,这表明脂联素可能在海马中表达；同时海马脂联素水平降低,而其受体AdipoR1和AdipoR2显著上调以补偿脂联素的不足；海马中ALDH2水平升高,其在抑郁发病中的作用尚不清楚。在心肌中,脂联素蛋白水平也显著降低,但其受体AdipoR1和AdipoR2以不同的趋势调控(AdipoR1减少和AdipoR2增加)；具有心血管保护作用的ALDH2显著降低。舍曲林治疗后CUMS组这些变化在一定程度上恢复了。综上所述,本研究证明应激下调了血清和心肌中HDL-C、脂联素和ALDH2的水平,增加了抑郁症并发心血管病的风险。舍曲林治疗抑郁症的同时,有潜在的保护心血管系统的作用。目前尚未见到运动干预抑郁模型代谢组的报道。本实验采用超高效液相色谱质谱联用技术(UPLC-MS)技术,结合PLS-DA高维统计分析,探讨强迫游泳对健康大鼠和抑郁模型大鼠血浆和尿液代谢轮廓的影响,观察强迫游泳对抑郁心血管疾病共病因子的影响。结果显示每天70分钟的强迫游泳造成了正常大鼠糖水偏好量的降低,以及海马中BDNF水平的下调；而另一方面,相对抑郁模型强迫游泳又显著上调了糖水偏好量和BDNF的水平。四组PLS-DA的代谢轮廓明显分开,模型第一个主成分主要体现了强迫游泳和CUMS对代谢物的同向调节作用,而第二个主成分则显示了二者的反向调节作用。通过S-plot筛选生物标志物以及糖脂生化检查,发现强迫游泳恢复了模型大鼠下降的脂联素水平和上调的葡萄糖水平。HDL-C、总胆固醇、溶血磷脂酰胆碱、缬氨酸、肌酐、色氨酸、苯丙氨酸等在空白组和模型组中有显著差异。图26幅,表7个,正文参考文献184篇。
[Abstract]:Depression will increase the incidence of cardiovascular disease, its mechanism is still under exploration. Chronic mild unpredictable stress (CUMS) model is a widely used depression model. Here we use a GC / MS based metabolic profile analysis method to explore the changes of myocardial metabolic profile in depression model rats. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DAA) were used to reveal the difference between the depression model and the control group. The results showed that the heart protective molecule (Glutamine P0. 019) and inosine (P0. 013), which were the main energy of heart, were found to be the main energy of the heart-fatty acid 9, 12-octadecadienoic acid, P0. 002, palmitic acid, P0. 006, and inosine P0. 013, respectively. P0. 030) and proline, a precursor of myocardial collagen, were down-regulated in depression model group. Based on the results of myocardial metabolism and the literature we speculated that glycolipid metabolism adiponectin which regulates glycolipid metabolism and acetaldehyde dehydrogenase (ALDH2) may play a role in depression cardiovascular disease. The glucose and lipid metabolism, acetaldehyde dehydrogenase 2 and adiponectin levels were measured by CUMS depression model. In addition, the effects of sertraline on the above indexes were studied. In the CUMS model group, the amount of glucose water preference and brain-derived neurotrophic factor (BDNF) in the hippocampus were significantly decreased, indicating that the successful establishment of the depression model, .CUMS, decreased the serum adiponectin. High density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglyceride (TGN), free fatty acid (FFA). Sertraline significantly recovered the serum adiponectin level of HDL-C after treatment. Adiponectin mRNAs were found in the hippocampus, indicating that adiponectin may be expressed in the hippocampus, and the level of adiponectin in hippocampus decreased, while its receptors AdipoR1 and AdipoR2 increased significantly to compensate for the deficiency of adiponectin. Its role in the pathogenesis of depression is unclear. The level of adiponectin protein also decreased significantly in myocardium, but its receptors AdipoR1 and AdipoR2 regulated the decrease of AdipoR1 and the increase of AdipoR2 in different trends, while ALDH2, which had cardiovascular protective effect, decreased significantly. These changes recovered to some extent in the CUMS group after sertraline treatment. In conclusion, this study demonstrated that stress down-regulated the levels of HDL-C, adiponectin and ALDH2 in serum and myocardium, and increased the risk of depression complicated with cardiovascular disease. Sertraline has the potential to protect the cardiovascular system while treating depression. At present, there is no report of metabolic group of exercise intervention depression model. The effect of forced swimming on plasma and urine metabolic profile in healthy and depressed rats was studied by using UPLC-MS and high dimensional statistical analysis of PLS-DA. To observe the effect of forced swimming on cofactors of depression and cardiovascular disease. The results showed that forced swimming for 70 minutes per day resulted in the decrease of sugar water preference and the down-regulation of BDNF level in the hippocampus of normal rats, and on the other hand, forced swimming in the depression model significantly up-regulated the glucose water preference and BDNF levels. The metabolic profile of PLS-DA in the four groups was obviously separated. The first principal component of the model mainly reflected the codirectional regulation of the metabolites by forced swimming and CUMS, while the second principal component showed the reverse regulation of the two. By S-plot screening of biomarkers and glycolipid biochemical tests, it was found that forced swimming restored the decreased adiponectin level and up-regulated glucose level. HDL-C, total cholesterol, lysophosphatidylcholine, valine, creatinine, tryptophan, total cholesterol, creatinine, tryptophan, total cholesterol, There were significant differences in phenylalanine between blank group and model group. There are 26 figures, 7 tables and 184 references.
【学位授予单位】：中南大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R749.4;R-332

【参考文献】