Chen Yinliang, Yang Jinbao, Wang Ying, Shen Weike, Liu Jinlin, Yuan Meng, Hao Xiaoyu, Zhong Li, Guo Rui
College of Life Sciences, Institute of Life Science and Green Development, Hebei University, Baoding, China.
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States.
Front Cardiovasc Med. 2022 Mar 21;9:835244. doi: 10.3389/fcvm.2022.835244. eCollection 2022.
Diabetic cardiomyopathy (DCM) is a primary cause of death in diabetic patients; however, its molecular mechanism is not yet clear, and there is no uniform standard for diagnosis. The aim of this study is to discover the pathogenesis and potential therapeutic targets of DCM through screening and analysis of differentially expressed genes (DEGs) in heart ventricles of DCM, and to testify the role of key hub genes in DCM-induced myocardial dysfunction. Datasets GSE4745 and GSE6880 were downloaded from the GEO database. The difference analysis, visual analysis, cluster analysis and enrichment analysis were performed by using R language, python scripts and bioinformatics software followed by the construction of protein-protein interaction (PPI) network to obtain hub genes. The DCM models were established by streptozocin (STZ) injection to the male mice. The cardiac function and the expressions of hub genes were examined by using echocardiography and real-time quantitative poly-merase chain reaction (RT-qPCR), followed by multiple statistical analyses. Bioinformatic results indicate that mitochondrial dysfunction, disturbed lipid metabolism and decreased collagen synthesis are the main causes of the DCM development. In particular, the hub gene that encodes Cytochrome P450 1A1 (CYP4501A1) enzyme has the highest connectivity in the interaction network, and is associated with mitochondrial homeostasis and energy metabolism. It plays a critical role in the oxidation of endogenous or exogenous substrates. Our RT-qPCR results confirmed that ventricular mRNA level was nearly 12-fold upregulated in DCM model compared to normal control, which was correlated with abnormal cardiac function in diabetic individuals. CYP4501A1 protein expression in mitochondria was also increased in diabetic hearts. However, we found no significant changes in collagen expressions in cardiac ventricles of mice with DCM. This study provided compact data support for understanding the pathogenesis of DCM. CYP4501A1 might be considered as a potential candidate targeting for DCM therapy. Follow-up animal and clinical verifications need to be further explored.
糖尿病性心肌病（DCM）是糖尿病患者死亡的主要原因；然而，其分子机制尚不清楚，且尚无统一的诊断标准。本研究旨在通过对DCM心室中差异表达基因（DEG）的筛选和分析，发现DCM的发病机制和潜在治疗靶点，并验证关键枢纽基因在DCM诱导的心肌功能障碍中的作用。数据集GSE4745和GSE6880从GEO数据库下载。使用R语言、Python脚本和生物信息学软件进行差异分析、可视化分析、聚类分析和富集分析，随后构建蛋白质-蛋白质相互作用（PPI）网络以获得枢纽基因。通过向雄性小鼠注射链脲佐菌素（STZ）建立DCM模型。使用超声心动图和实时定量聚合酶链反应（RT-qPCR）检测心功能和枢纽基因的表达，随后进行多种统计分析。生物信息学结果表明，线粒体功能障碍、脂质代谢紊乱和胶原蛋白合成减少是DCM发展的主要原因。特别是，编码细胞色素P450 1A1（CYP4501A1）酶的枢纽基因在相互作用网络中具有最高的连接性，并与线粒体稳态和能量代谢相关。它在内源性或外源性底物的氧化中起关键作用。我们的RT-qPCR结果证实，与正常对照相比，DCM模型中心室mRNA水平上调了近12倍，这与糖尿病个体的心功能异常相关。糖尿病心脏中线粒体中CYP4501A1蛋白表达也增加。然而，我们发现DCM小鼠心室中的胶原蛋白表达没有显著变化。本研究为理解DCM的发病机制提供了确凿的数据支持。CYP4501A1可能被视为DCM治疗的潜在候选靶点。后续的动物和临床验证需要进一步探索。
