Abstract
Objective: The vulnerability of atherosclerotic plaques is among the leading cause of ischemic stroke. High wall shear stress (WSS) promotes the instability of atherosclerotic plaques by directly imparting mechanical stimuli, but the specific mechanisms remain unclear. We speculate that modulation of mechanosensitive genes may play a vital role in accelerating the development of plaques. The purpose of this study was to find mechanosensitive genes in vascular endothelial cells (ECs) through combining microarray data with bioinformatics technology and further explore the underlying dynamics–related mechanisms that cause the progression and destabilization of atherosclerotic plaques. Methods: Microarray data sets for human vascular ECs under high and normal WSS were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified through the R language. The performance of enrichment analysis and protein–protein interaction (PPI) network presented the biological function and signaling pathways of the DEGs. Hub genes were identified based on the PPI network and validated by GEO data sets. Predicted transcription factor (TF) genes and miRNAs interaction with potential mechanosensitive genes were identified by NetworkAnalyst. Results: A total of 260 DEGs, 121 upregulated and 139 downregulated genes, were screened between high and normal WSS from GSE23289. A total of 10 hub genes and four cluster modules were filtered out based on the PPI network. The enrichment analysis showed that the biological functions of the hub genes were mainly involved in responses to unfolded protein and topologically incorrect protein, and t to endoplasmic reticulum stress. The significant pathways associated with the hub genes were those of protein processing in the endoplasmic reticulum, antigen processing, and presentation. Three out of the 10 hub genes, namely, activated transcription factor 3 (ATF3), heat shock protein family A (Hsp70) member 6 (HSPA6), and dual specificity phosphatase 1 (DUSP1, also known as CL100, HVH1, MKP-1, PTPN10), were verified in GSE13712. The expression of DUSP1 was higher in the senescent cell under high WSS than that of the young cell. The TF–miRNA–mechanosensitive gene coregulatory network was constructed. Conclusion: In this work, we identified three hub genes, ATF3, HSPA6, and DUSP1, as the potential mechanosensitive genes in the human blood vessels. DUSP1 was confirmed to be associated with the senescence of vascular ECs. Therefore, these three mechanosensitive genes may have emerged as potential novel targets for the prediction and prevention of ischemic stroke. Furthermore, the TF–miRNA–mechanosensitive genes coregulatory network reveals an underlying regulatory mechanism and the pathways to control disease progression.
Highlights
Atherosclerosis (AS), the underlying cause of ischemic stroke, is the most common cause of morbidity, mortality, and disability in the world, which has become a major global health problem due to the lack of effective methods for screening at an early stage and limited therapeutic strategies
The data set GSE23289, which included eight samples divided into two groups (HUVECs were cultured under the normal and the high wall shear stress (WSS), respectively), identified and analyzed the differentially expressed genes (DEGs) using the R package
We found that 241 gene ontology (GO)-biological process (BP), 16 GO-molecular function (MF), and 16 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were highly enriched for these DEGs (Supplementary Table 2)
Summary
Atherosclerosis (AS), the underlying cause of ischemic stroke, is the most common cause of morbidity, mortality, and disability in the world, which has become a major global health problem due to the lack of effective methods for screening at an early stage and limited therapeutic strategies. Recent molecular and cellular studies have begun to elucidate that low shear stress acting directly on vascular ECs leads to the formation of atherosclerosis and the development of thin fibrous caps. It promotes the deposition of particulate matter on the arterial wall and the accumulation of plaque, resulting from persistent changes of inflammation, oxidative stress, and proliferation in ECs (Feldman et al, 2002; Chatzizisis et al, 2007; Milkiewicz et al, 2008; Hsu et al, 2019). The discovery of novel mechanosensitive genes and their potential functional mechanisms in ECs have great implications in the individualized early diagnosis and precision treatment of ischemic stroke
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