Department of Biomedical Engineering, Schools of Medicine and Engineering, University of Alabama at Birmingham, Birmingham, Alabama.
Am J Physiol Heart Circ Physiol. 2021 May 1;320(5):H2044-H2057. doi: 10.1152/ajpheart.00635.2020. Epub 2021 Apr 9.
Major depressive disorder (MDD) is an independent risk factor for cardiovascular disease (CVD) and its complications; however, causal mechanisms remain unclear. In the present study, we investigate cardiac structural and functional alterations and associated changes in myocardial glycosaminoglycans (GAGs) disaccharide profile in mice that exhibit depression-like behavior. Mice were assigned to the chronic mild stress (CMS) group and nonstress control group (CT). The CMS group was exposed to a series of mild, unpredictable stressors for 7 wk. Mice in the CMS group show a significant decrease in protein expression of hippocampal brain-derived neurotrophic factor (BDNF) and exhibit depression-like behavioral changes, such as learned helplessness and decreased exploration behavior, as compared with the control group. Although cardiac function remained unchanged between the groups, echocardiography analysis showed slightly increased left ventricular wall thickness in the CMS group. Furthermore, the CMS group shows an increase in cardiomyocyte cross-sectional area and an associated decrease in BDNF protein expression and increase in IL-6 mRNA expression, when compared with control mice. GAG disaccharide analysis of the left ventricles of the CMS and CT mice revealed an elevation in heparan (HS) and chondroitin sulfate (CS) content in the CMS hearts (35.3% and 17.9%, respectively, vs. control group). Furthermore, we also observed that unsulfated or monosulfated disaccharides were the most abundant units; however, we did not find any significant difference in mole percent or sulfation pattern of HS/CS disaccharides between the groups. The current investigation highlights a need for further research to explore the relationship between cardiac GAGs biology and myocardial remodeling as a causal mechanism that underlie cardiovascular complications in patients with MDD. Comorbidity between depression and CVD is well established, whereas its etiology, especially the role of nonfibrous components (proteoglycans/GAGs) of the extracellular matrix, is unexplored. To the best of our knowledge, this is the first study to characterize cardiac proteoglycan/glycosaminoglycan profile in response to depression-like behavioral changes in mice. We observed that chronic mild stress (CMS)-induced depression-like behavior and alterations in glycosaminoglycan profile were associated with structural changes in the heart.
重度抑郁症（MDD）是心血管疾病（CVD）及其并发症的独立危险因素；然而，因果机制仍不清楚。在本研究中，我们研究了表现出抑郁样行为的小鼠的心脏结构和功能改变以及心肌糖胺聚糖（GAG）二糖谱的相关变化。将小鼠分为慢性轻度应激（CMS）组和非应激对照组（CT）。CMS 组接受了为期 7 周的一系列轻度、不可预测的应激源。与对照组相比，CMS 组小鼠海马脑源性神经营养因子（BDNF）的蛋白表达显著下降，并表现出抑郁样行为变化，如习得性无助和探索行为减少。尽管两组之间的心脏功能保持不变，但超声心动图分析显示 CMS 组左心室壁厚度略有增加。此外，与对照组小鼠相比，CMS 组的心肌细胞横截面积增加，BDNF 蛋白表达降低，IL-6 mRNA 表达升高。CMS 和 CT 小鼠左心室 GAG 二糖分析显示，CMS 心脏中的肝素（HS）和软骨素硫酸盐（CS）含量升高（分别为 35.3%和 17.9%，与对照组相比）。此外，我们还观察到未硫酸化或单硫酸化二糖是最丰富的单位；然而，我们没有发现两组 HS/CS 二糖的摩尔百分比或硫酸化模式有任何显著差异。目前的研究强调需要进一步研究，以探讨心脏 GAG 生物学与心肌重构之间的关系，作为 MDD 患者心血管并发症的潜在因果机制。抑郁和 CVD 的合并症已得到充分确立，但其病因，特别是细胞外基质中非纤维成分（蛋白聚糖/GAG）的作用，尚未得到探索。据我们所知，这是第一项研究描述了在小鼠抑郁样行为变化中对心脏蛋白聚糖/糖胺聚糖谱的特征。我们观察到慢性轻度应激（CMS）诱导的抑郁样行为和糖胺聚糖谱的改变与心脏结构变化有关。
