Qin Cheng, Wang Yujia, Zhang Yang, Zhu Yan, Wang Yabin, Cao Feng
Department of Cardiology, National Clinical Research Center for Geriatric Diseases and Second Medical Center of Chinese PLA General Hospital, Beijing, China.
Nankai University School of Medicine, Nankai University, Tianjin, China.
Front Genet. 2023 Jan 10;13:1095428. doi: 10.3389/fgene.2022.1095428. eCollection 2022.
Growing evidence has supported that chronic psychological stress would cause heart damage, However the mechanisms involved are not clear and effective interventions are insufficient. Cannabinoid type 2 receptor (CB2R) can be a potential treatment for cardiac injury. This study is aimed to investigate the protective mechanism of CB2R agonist against chronic psychological stress-induced cardiac injury. A mouse chronic psychological stress model was constructed based on a chronic unpredictable stress pattern. Mice were performed a three-week psychological stress procedure, and cardiac tissues of them were collected for whole-transcriptome sequencing. Overlap analysis was performed on differentially expressed mRNAs (DE-mRNAs) and ER stress-related genes (ERSRGs), and bioinformatic methods were used to predict the ceRNA networks and conduct pathway analysis. The expressions of the DE-ERSRGs were validated by RT-qPCR. In the comparison of DE mRNA in Case group, Control group and Treatment group, three groups of ceRNA networks and ceRNA (circ) networks were constructed. The DE-mRNAs were mainly enriched in chromatid-relevant terms and Hematopoietic cell lineage pathway. Additionally, 13 DE-ERSRGs were obtained by the overlap analysis, which were utilized to establish a ceRNA network with 15 nodes and 14 edges and a ceRNA (circ) network with 23 nodes and 28 edges. Furthermore, four DE-ERSRGs (Cdkn1a, Atf3, Fkbp5, Gabarapl1) in the networks were key, which were mainly enriched in response to extracellular stimulus, response to nutrient levels, cellular response to external stimulus, and FoxO signaling pathway. Finally, the RT-qPCR results showed almost consistent expression patterns of 13 DE-ERSRGs between the transcriptome and tissue samples. The findings of this study provide novel insights into the molecular mechanisms of chronic psychological stress-induced cardiac diseases and reveal novel targets for the cardioprotective effects of CB2R agonists.
越来越多的证据支持慢性心理应激会导致心脏损伤，然而其涉及的机制尚不清楚，有效的干预措施也不足。2型大麻素受体（CB2R）可能是治疗心脏损伤的一种潜在方法。本研究旨在探讨CB2R激动剂对慢性心理应激诱导的心脏损伤的保护机制。基于慢性不可预测应激模式构建小鼠慢性心理应激模型。对小鼠进行为期三周的心理应激程序，并收集其心脏组织进行全转录组测序。对差异表达的mRNA（DE-mRNA）和内质网应激相关基因（ERSRG）进行重叠分析，并使用生物信息学方法预测ceRNA网络并进行通路分析。通过RT-qPCR验证DE-ERSRG的表达。在病例组、对照组和治疗组的DE mRNA比较中，构建了三组ceRNA网络和ceRNA（circ）网络。DE-mRNA主要富集在与染色单体相关的术语和造血细胞谱系通路中。此外，通过重叠分析获得了13个DE-ERSRG，利用它们建立了一个具有15个节点和14条边的ceRNA网络以及一个具有23个节点和28条边的ceRNA（circ）网络。此外，网络中的四个DE-ERSRG（Cdkn1a、Atf3、Fkbp5、Gabarapl1）是关键的，它们主要富集在对细胞外刺激的反应、对营养水平的反应、细胞对外部刺激的反应以及FoxO信号通路中。最后，RT-qPCR结果显示转录组和组织样本中13个DE-ERSRG的表达模式几乎一致。本研究结果为慢性心理应激诱导的心脏病的分子机制提供了新的见解，并揭示了CB2R激动剂心脏保护作用的新靶点。
