通过信息学分析鉴定肺动脉高压中与 Zip8 相关的枢纽基因。
Identification of Zip8-correlated hub genes in pulmonary hypertension by informatic analysis.
机构信息
College of Pharmacy, Xinxiang Medical University, Xinxiang, China.
Xinxiang Key Laboratory of Vascular Remodeling Intervention and Molecular Targeted Therapy Drug Development, Xinxiang, China.
出版信息
PeerJ. 2023 Aug 28;11:e15939. doi: 10.7717/peerj.15939. eCollection 2023.
BACKGROUND
Pulmonary hypertension (PH) is a syndrome characterized by marked remodeling of the pulmonary vasculature and increased pulmonary vascular resistance, ultimately leading to right heart failure and even death. The localization of Zrt/Irt-like Protein 8 (ZIP8, a metal ion transporter, encoded by SLC39A8) was abundantly in microvasculature endothelium and its pivotal role in the lung has been demonstrated. However, the role of Zip8 in PH remains unclear.
METHODS
Bioinformatics analysis was employed to identify SLC39A8 expression patterns and differentially expressed genes (DEGs) between PH patients and normal controls (NC), based on four datasets (GSE24988, GSE113439, GSE117261, and GSE15197) from the Biotechnology Gene Expression Omnibus (NCBI GEO) database. Gene set enrichment analysis (GSEA) was performed to analyze signaling pathways enriched for DEGs. Hub genes were identified by cytoHubba analysis in Cytoscape. Reverse transcriptase-polymerase chain reaction was used to validate SLC39A8 and its correlated metabolic DEGs expression in PH (SU5416/Hypoxia) mice.
RESULTS
SLC39A8 expression was downregulated in PH patients, and this expression pattern was validated in PH (SU5416/Hypoxia) mouse lung tissue. SLC39A8-correlated genes were mainly enriched in the metabolic pathways. Within these SLC39A8-correlated genes, 202 SLC39A8-correlated metabolic genes were screened out, and seven genes were identified as SLC39A8-correlated metabolic hub genes. The expression patterns of hub genes were analyzed between PH patients and controls and further validated in PH mice. Finally, four genes (Fasn, Nsdhl, Acat2, and Acly) were downregulated in PH mice. However, there were no significant differences in the expression of the other three hub genes between PH mice and controls. Of the four genes, Fasn and Acly are key enzymes in fatty acids synthesis, Nsdhl is involved in cholesterol synthesis, and Acat2 is implicated in cholesterol metabolic transformation. Taken together, these results provide novel insight into the role of Zip8 in PH.
背景
肺动脉高压（PH）是一种以肺血管显著重塑和肺血管阻力增加为特征的综合征，最终导致右心衰竭甚至死亡。锌转运蛋白 8（ZIP8，一种由 SLC39A8 编码的金属离子转运蛋白）在微血管内皮中大量存在，其在肺部的关键作用已得到证实。然而，Zip8 在 PH 中的作用尚不清楚。
方法
采用生物信息学分析方法，基于生物技术基因表达综合数据库（NCBI GEO）中的四个数据集（GSE24988、GSE113439、GSE117261 和 GSE15197），鉴定 PH 患者和正常对照（NC）之间 SLC39A8 的表达模式和差异表达基因（DEGs）。采用基因集富集分析（GSEA）分析 DEGs 富集的信号通路。通过 Cytoscape 中的 cytoHubba 分析鉴定枢纽基因。采用逆转录聚合酶链反应（RT-PCR）验证 PH（SU5416/缺氧）小鼠中 SLC39A8 及其相关代谢 DEGs 的表达。
结果
PH 患者 SLC39A8 表达下调，这一表达模式在 PH（SU5416/缺氧）小鼠肺组织中得到验证。SLC39A8 相关基因主要富集在代谢途径中。在这些 SLC39A8 相关基因中，筛选出 202 个 SLC39A8 相关代谢基因，鉴定出 7 个 SLC39A8 相关代谢枢纽基因。对枢纽基因在 PH 患者和对照之间的表达模式进行分析，并在 PH 小鼠中进一步验证。最后，在 PH 小鼠中发现 4 个基因（Fasn、Nsdhl、Acat2 和 Acly）表达下调。然而，在 PH 小鼠和对照组之间，其他三个枢纽基因的表达没有显著差异。这四个基因中，Fasn 和 Acly 是脂肪酸合成的关键酶，Nsdhl 参与胆固醇合成，Acat2 参与胆固醇代谢转化。综上所述，这些结果为 Zip8 在 PH 中的作用提供了新的见解。
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