Machine Learning and Network Methods for Biology and Medicine 2021View this Special Issue
Research Article | Open Access
Rui Lian, Guochao Zhang, Shengtao Yan, Lichao Sun, Guoqiang Zhang, "Identification of Molecular Regulatory Features and Markers for Acute Type A Aortic Dissection", Computational and Mathematical Methods in Medicine, vol. 2021, Article ID 6697848, 14 pages, 2021. https://doi.org/10.1155/2021/6697848
Identification of Molecular Regulatory Features and Markers for Acute Type A Aortic Dissection
Background. Acute type A aortic dissection (ATAAD) is one of the most lethal cardiovascular diseases, and its molecular mechanism remains unclear. Methods. Differentially expressed genes (DEGs) between ATAAD and control were detected by limma R package in GSE52093, GSE153434, GSE98770, and GSE84827, respectively. The coexpression network of DEGs was identified by the WGCNA package. Enrichment analysis was performed for module genes that were positively correlated with ATAAD using clusterProfiler R package. In addition, differentially methylated markers between aortic dissection and control were identified by ChAMP package. After comparing with ATAAD-related genes, a protein-protein interaction (PPI) network was established based on the STRING database. The genes with the highest connectivity were identified as hub genes. Finally, differential immune cell infiltration between ATAAD and control was identified by ssGSEA. Results. From GSE52093 and GSE153434, 268 module genes were obtained with consistent direction of differential expression and high correlation with ATAAD. They were significantly enriched in T cell activation, HIF-1 signaling pathway, and cell cycle. In addition, 2060 differentially methylated markers were obtained from GSE84827. Among them, 77 methylation markers were ATAAD-related DEGs. Using the PPI network, we identified MYC, ITGA2, RND3, BCL2, and PHLPP2 as hub genes. Finally, we identified significantly differentially infiltrated immune cells in ATAAD. Conclusion. The hub genes we identified may be regulated by methylation and participate in the development of ATAAD through immune inflammation and oxidative stress response. The findings may provide new insights into the molecular mechanisms and therapeutic targets for ATAAD.
Aortic dissection (AD) is a serious invasive vascular disease with high mortality and limited treatment options . The incidence of aortic dissection ranges from between 3.5 and 6/100,000 person-years in the general population to as high as 10/100,000 person-years in the elderly . Usually, aortic dissection is caused by intimal tear, which further causes blood to flow into the media layer of the aorta, resulting in the separation of the layers within the aortic wall . When the ascending aorta is involved, this dissection is known as Stanford type A aortic dissection (STAAD) . Surgical mortality for acute Stanford type A aortic dissection (ATAAD) is relatively high, despite advances in medical and surgical treatment over the past 30 years . Theoretically, once acute STAAD is diagnosed, patients should undergo emergency surgical treatment immediately . However, limited by geographical, economic, and technical conditions, not all patients can receive timely treatment.
Early clinical symptoms of ATAAD may mimic those of other diseases, such as acute coronary syndrome, pulmonary embolism, or pneumothorax, often leading to delayed diagnosis [7–9]. When ATAAD is detected early and treated promptly, the chance of survival is greatly improved [10–12]. However, even in experienced cardiac centers, the early mortality rate for surgical treatment of acute aortic dissection is around 10%, and many patients still die before surgery . Therefore, we believe that identifying early prognostic biomarkers can leverage patient characteristics and symptoms to optimize treatment strategies [14, 15].
At present, the molecular mechanism of ATAAD remains unclear. Chronic inflammation of the aortic lining has been reported to cause aneurysm growth, leading to aortic dissection [16–18]. In animal models, adventitial inflammation characterized by neutrophil aggregation can promote tissue damage, leading to aortic dilation and rupture . In addition, the medial integrity maintained by collagen and elastin cross-linking is one of the keys in preventing aortic dissection . Bone marrow mesenchymal stem cells are also potential contributors to aortic repair .
It is increasingly believed that human disease states are not caused by a single change but by the multifactorial regulation of biological systems . In many cardiovascular diseases, important epigenetic modifications, including methylation, have been shown to affect the development or progression of the disease . Methylation modification of the gene may serve as a diagnostic and prognostic marker in patients with aortic dissection .
Weighted gene coexpression network analysis (WGCNA) is a widely used method to build coexpression pairwise correlation matrices . Exclusively based on coexpression analysis, it will better represent genes with a small effect size acting together . WGCNA provides a systems-level insight into the signaling networks that may be associated with a phenotype of interest .
The network-based approach provided a powerful option for systematic analysis to identify candidate target genes. The aim of this study was to identify DEGs and related methylation modifications in ATAAD compared with healthy controls. At the same time, the molecular mechanisms involved in gene expression changes were discussed. This study is helpful in identifying new DNA methylation markers and improving both our understanding and the treatment level of ATAAD.
2. Materials and Methods
2.1. Data Sources
Aortic dissection data were collected from the Gene Expression Omnibus (GEO) database. We screened datasets with a sample size greater than 5. GSE52093 included gene expression data of dissected ascending aorta from patients with acute Stanford type A aortic dissection () and normal controls (). GSE98770 included gene expression data of dissected ascending aorta from patients with acute type A aortic dissection (ATAAD) () and gene expression data of nondissected ascending aorta obtained from transplant donors (). GSE153434 included gene expression data of dissected ascending aorta from patients with Stanford type A aortic dissection () and normal control samples ().
2.2. Differential Gene Expression Analysis
The differential expression analysis between aortic dissection and healthy controls was performed by using the R software package limma . The genes with (up-/downregulated) were extracted as differentially expressed genes (DEGs) [29, 30].
A gene coexpression network was constructed through the WGCNA package  using differentially expressed genes. The genes with similar expression behavior were divided into different modules. After determining the soft thresholding, the network was developed. Module-trait relationships were calculated using a Pearson correlation between modules and clinical trait. value < 0.05 was regarded as significant.
2.4. Enrichment Analysis
Module genes were analyzed using the clusterProfiler R package  for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The Gene Ontology (GO) enrichment results included the biological process (BP), cellular component (CC), and molecular function (MF) . A term with was considered a functionally enriched term.
2.5. Methylation Data Analysis
GSE84274 included methylation profiling of ascending aorta from 6 normal and 12 aortic dissection patients. The difference of methylation sites between aortic dissection and healthy controls was analyzed by the ChAMP software package . Adjust (adj) value < 0.05 was regarded as significant.
2.6. PPI Network Construction
We utilized the Search Tool for the Retrieval of Interacting Genes (STRING) database (http://string-db.org) to construct a protein-protein interaction (PPI) network for module genes, with a . The PPI network was visualized through Cytoscape software (Version 3.7.0) [35–38]. The genes with the top 5 degrees for connecting other genes in the network were considered as hub genes.
2.7. Single-Sample Gene Set Enrichment Analysis (ssGSEA)
To investigate the immune infiltration landscape of acute type A aortic dissection, ssGSEA was performed to evaluate the level of immune infiltration in a sample according to immune cell-specific marker genes . Infiltration levels for immune cells were quantified using the ssGSEA implementation in gsva R package. value < 0.05 was considered significant.
3.1. Coexpression Network of Differentially Expressed Genes
To obtain genes related to acute type A aortic dissection, we compared them with healthy controls. A total of 4913 differentially expressed genes were obtained in GSE52093 (Figure 1(a)). We selected as the soft thresholding to ensure that the network can obey the scale-free criteria (Figure 1(b)). The created network included three modules (Figure 1(c)). Then, 4682 differentially expressed genes were obtained in GSE153434 (Figure 1(d)). Setting as the soft thresholding, we got 9 modules (Figures 1(e) and 1(f)).
3.2. Biological Functions of Module Genes
The correlation analysis found that MEturquoise (module 2) of GSE52093 had the strongest correlation with ATAAD (Figure 2(a)). MEbrown (module 1), MEyellow (module 5), MEgreen (module 4), and MEblack (module 7) in GSE153434 were positively correlated with ATAAD (Figure 2(b)). Then, we obtained 268 common genes that expressed in the same direction (upregulated or downregulated expression) in these modules (Figure 2(c)). They may have a stronger association with ATAAD. Enrichment analysis revealed that common genes were mainly enriched in response to oxygen levels, T cell activation, leukocyte migration, and NIK/NF-kappaB signaling biological functions (Figure 2(d)). In addition, the p53 signaling pathway, the HIF-1 signaling pathway, the FoxO signaling pathway, and the cell cycle of the KEGG pathways were also significantly enriched (Figure 2(e)).
3.3. Methylated ATAAD-Related Genes
By comparing the differences between aortic dissection patients and controls, we obtained 46,845 differentially methylated positions (DMPs) (Figure 3(a)). Most DMPs were concentrated at the chr1 position (Figure 3(b)). We identified 2060 genes with opposite methylation and transcription levels as methylation markers (Figure 3(c)). Interestingly, among these methylation markers, we found that 77 genes were common genes (Figure 3(d)). Using the PPI network, we identified the top five genes with the highest connectivity as hub genes (Figure 4(a)). Compared with the control, MYC, ITGA2, and RND3 were upregulated in ATAAD, and BCL2 and PHLPP2 were downregulated (Figure 4(b)). The AUC values of hub genes were greater than 0.8 in both datasets, which may have a diagnostic role for ATAAD (Figure 4(c)).
3.4. Immune Cell Infiltration Difference in ATAAD
Differences in immune cell infiltration were found in ATAAD patients compared with controls (Figure 5(a)). Th1 cells, B cells, T helper cells, T cells, DC, iDC, Tgd, eosinophils, and NK cells were significantly downregulated. The different directions of Th1 cells, Tgd, T cells, T helper cells, iDC, DC, and B cells were consistent in GSE52093, GSE98770, and GSE153434 (Figure 5(b)). These immune cells were clustered into four categories, and there was a positive or negative correlation between the cells (Figure 5(c)). In ATAAD, iDC and macrophages had the strongest positive correlation, while in the control group, iDC and neutrophils had the strongest positive correlation (Figure 5(d)). The correlation analysis results between immune cells and hub genes showed that Th2 cells had the strongest correlation with ITGA2, while NK cells and Th17 cells had the strongest correlation with BCL2 (Figure 5(e)).
Repair of acute type A aortic dissection remains a challenge with high operative mortality . As ATAAD is one of the most elusive and life-threatening vascular diseases, a better understanding of the molecular mechanisms of ATAAD is essential to improve clinical efficacy. In this study, genes with higher correlation with ATAAD were identified by comparing gene expression differences between ATAAD and controls. These genes were mainly associated with immune inflammation. The genes modified by methylation were screened as important genes to construct a PPI network, and five hub genes were identified. In addition, by comparing the difference of immune cell infiltration between ATAAD and control, we also similarly found that immune cells played an important regulatory role in the disease process .
Among the ATAAD-related biological functions we identified, T cell activation had been confirmed by other studies [42–44]. Different T cell subsets may play different roles in the development of ATAAD. Elevated white blood cell count is associated with poor prognosis in ATAAD [45, 46]. Inflammatory cells and cytokines, white blood cell count, and neutrophil count have been reported to be responsible for preoperative hypoxemia in ATAAD . Increased inflammatory response is a key factor in promoting the occurrence and development of ATAAD . High inflammatory biomarkers were observed in patients at onset, indicating that the inflammatory response started early in ATAAD . More severe inflammation and oxidative stress reactions occur in obese ATAAD patients . Inflammation and hypoxia are often interdependent . Our findings also suggested that the HIF-1 signaling pathway was activated during ATAAD, thereby aggravating aortic dissection . Therefore, we believe that inflammation and oxidative stress may play an important role in the process of ATAAD.
Notably, upregulated MYC, ITGA2, and RND3 and downregulated BCL2 and PHLPP2 were identified as hub genes of the PPI network. Studies had shown that MYC was indeed upregulated in ATAAD . MYC signaling is involved in vascular smooth muscle cell (VSMC) dysfunction, vasoconstriction, and vascular remodeling in aortic dissection . ITGA2 interacts with collagen in tumors, promotes cell migration, and promotes apoptosis-free resistance [54, 55]. Although there was no direct evidence that ITGA2 was associated with ATAAD, aortic disease was associated with collagen content or structure . It suggested that ITGA2 may act on the development of ATAAD through collagen. In addition, ITGA3 and ITGA5 were identified as new biomarkers for the onset of acute aortic dissection . RND3 played an important role in blocking cell cycle distribution, inhibiting cell growth, and inducing apoptosis and differentiation [58, 59]. Abnormal expression of RND3 may be the main cause of some cardiovascular diseases . The BCL2 protein family influenced the apoptosis of vascular smooth muscle cells in human aortic dissection . PHLPP2 had been reported as a therapeutic target for cancer and cardiovascular diseases [62, 63]. Although no relationship between PHLPP2 and ATAAD had been reported, our findings suggested that its downregulation may be a risk factor for ATAAD.
Most studies used microarray technology to compare diseased and normal aortic tissues and found some signs of ATAAD differentially expressed genes [16, 22]. However, the regulatory mechanisms of differentially expressed genes remain to be determined. The hub genes identified in this study were all modified by methylation. Alterations in gene methylation may mediate the involvement of vascular smooth muscle cells and inflammatory cells in the development of aortic dissection . At present, there are relatively few studies on the regulation of methylation in ATAAD, and we believe that hub genes may be regulated by methylation and thus participate in the progress of ATAAD.
Like other studies, our study also had some limitations. First, these results were obtained only by bioinformatics analysis and were not confirmed by molecular experiments. In addition, although hub genes, potential methylation regulators, and related biological functions of ATAAD had been identified, there was still a long way to go to translate these findings into clinical applications.
It was worth emphasizing that comprehensive network analysis provided a new perspective to understand the molecular basis of ATAAD and promised to elucidate the complex relationship between DEGs in complex diseases. Hub genes were regulated by methylation and participated in the development of ATAAD through immune inflammation and oxidative stress responses. This study will help to identify new DNA methylation markers and improve the understanding and treatment level of ATAAD.
There were a large number of differentially expressed genes in ATAAD patients, which mainly regulated immune inflammation and oxidative stress functions. In particular, MYC, ITGA2, RND3, BCL2, and PHLPP2 were regulated by methylation in ATAAD. Differential expression of these genes may be associated with the progression of ATAAD, which may be a diagnostic biomarker and a new therapeutic target for ATAAD.
The data used in our study could be found in GSE52093 and GSE98770.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
This work was funded by the National Key R&D Program of China (2019YFF0216303).
- G. Lian, X. Li, L. Zhang et al., “Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway,” eBioMedicine, vol. 49, pp. 291–304, 2019.
- P. Chiu and D. C. Miller, “Evolution of surgical therapy for Stanford acute type A aortic dissection,” Annals of cardiothoracic surgery, vol. 5, no. 4, pp. 275–295, 2016.
- S. Parve, B. A. Ziganshin, and J. A. Elefteriades, “Overview of the current knowledge on etiology, natural history and treatment of aortic dissection,” The Journal of Cardiovascular Surgery, vol. 58, no. 2, pp. 238–251, 2017.
- W. J. Jiang, W. H. Ren, X. J. Liu et al., “Disruption of mechanical stress in extracellular matrix is related to Stanford type A aortic dissection through down-regulation of Yes-associated protein,” Aging (Albany NY), vol. 8, no. 9, pp. 1923–1939, 2016.
- E. Moeller, M. Nores, and S. C. Stamou, “Repair of acute type-A aortic dissection in the present era: outcomes and controversies,” AORTA Journal, vol. 7, no. 6, pp. 155–162, 2019.
- M. A. Coady, J. A. Rizzo, L. J. Goldstein, and J. A. Elefteriades, “Natural history, pathogenesis, and etiology of thoracic aortic aneurysms and dissections,” Cardiology Clinics, vol. 17, no. 4, pp. 615–635, 1999, vii.
- T. Fukui, “Management of acute aortic dissection and thoracic aortic rupture,” Journal of Intensive Care, vol. 6, no. 1, p. 15, 2018.
- P. C. Spittell, J. A. Spittell Jr., J. W. Joyce et al., “Clinical features and differential diagnosis of aortic dissection: experience with 236 cases (1980 through 1990),” Mayo Clinic Proceedings, vol. 68, no. 7, pp. 642–651, 1993.
- R. E. Clough and C. A. Nienaber, “Management of acute aortic syndrome,” Nature Reviews. Cardiology, vol. 12, no. 2, pp. 103–114, 2015.
- C. A. Nienaber, R. E. Clough, N. Sakalihasan et al., “Aortic dissection,” Nature Reviews. Disease Primers, vol. 2, no. 1, p. 16053, 2016.
- P. G. Hagan, C. A. Nienaber, E. M. Isselbacher et al., “The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease,” JAMA, vol. 283, no. 7, pp. 897–903, 2000.
- F. Luo, X. L. Zhou, J. J. Li, and R. T. Hui, “Inflammatory response is associated with aortic dissection,” Ageing Research Reviews, vol. 8, no. 1, pp. 31–35, 2009.
- Y. Okita, “Current surgical results of acute type A aortic dissection in Japan,” Annals of cardiothoracic surgery, vol. 5, no. 4, pp. 368–376, 2016.
- C. Gu, X. Shi, C. Dai et al., “RNA m6A modification in cancers: molecular mechanisms and potential clinical applications,” The Innovation, vol. 1, no. 3, p. 100066, 2020.
- C. Gu and C. Chen, “Methylation in lung cancer: a brief review,” Methods in Molecular Biology, vol. 2204, pp. 91–97, 2020.
- N. Kimura, K. Futamura, M. Arakawa et al., “Gene expression profiling of acute type A aortic dissection combined with in vitro assessment,” European Journal of Cardio-Thoracic Surgery, vol. 52, no. 4, pp. 810–817, 2017.
- T. A. Kermani, K. J. Warrington, C. S. Crowson et al., “Predictors of dissection in aortic aneurysms from giant cell arteritis,” Journal of Clinical Rheumatology, vol. 22, no. 4, pp. 184–187, 2016.
- F. Tavora, J. Jeudy, C. Gocke, and A. Burke, “Takayasu aortitis with acute dissection and hemopericardium,” Cardiovascular Pathology, vol. 14, no. 6, pp. 320–323, 2005.
- A. Anzai, M. Shimoda, J. Endo et al., “Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture,” Circulation Research, vol. 116, no. 4, pp. 612–623, 2015.
- L. F. Hiratzka, G. L. Bakris, J. A. Beckman et al., “2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology,American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons,and Society for Vascular Medicine,” Journal of the American College of Cardiology, vol. 55, no. 14, pp. e27–e129, 2010.
- J. Yang, S. Zou, M. Liao, and L. Qu, “Transcriptome sequencing revealed candidate genes relevant to mesenchymal stem cells’ role in aortic dissection patients,” Molecular Medicine Reports, vol. 17, no. 1, pp. 273–283, 2018.
- S. Pan, D. Wu, A. E. Teschendorff et al., “JAK2-centered interactome hotspot identified by an integrative network algorithm in acute Stanford type A aortic dissection,” PLoS One, vol. 9, no. 2, article e89406, 2014.
- A. Boileau, M. E. Lindsay, J. B. Michel, and Y. Devaux, “Epigenetics in ascending thoracic aortic aneurysm and dissection,” AORTA Journal, vol. 6, no. 1, pp. 1–12, 2018.
- N. Li, H. Lin, H. Zhou et al., “Efficient detection of differentially methylated regions in the genome of patients with thoracic aortic dissection and association with MMP2 hypermethylation,” Experimental and Therapeutic Medicine, vol. 20, no. 2, pp. 1073–1081, 2020.
- A. S. Feltrin, A. C. Tahira, S. N. Simões, H. Brentani, and D. C. Martins Jr., “Assessment of complementarity of WGCNA and NERI results for identification of modules associated to schizophrenia spectrum disorders,” PLoS One, vol. 14, no. 1, article e0210431, 2019.
- P. Chaste, L. Klei, S. J. Sanders et al., “A genome-wide association study of autism using the Simons Simplex Collection: does reducing phenotypic heterogeneity in autism increase genetic homogeneity?” Biological Psychiatry, vol. 77, no. 9, pp. 775–784, 2015.
- W. Liang, F. Sun, Y. Zhao, L. Shan, and H. Lou, “Identification of susceptibility modules and genes for cardiovascular disease in diabetic patients using WGCNA analysis,” Journal Diabetes Research, vol. 2020, article 4178639, pp. 1–11, 2020.
- M. E. Ritchie, B. Phipson, D. I. Wu et al., “limma powers differential expression analyses for RNA-sequencing and microarray studies,” Nucleic acids research, vol. 43, no. 7, article e47, 2015.
- C. Gu, X. Shi, Z. Huang et al., “A comprehensive study of construction and analysis of competitive endogenous RNA networks in lung adenocarcinoma,” Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics, vol. 1868, no. 8, article 140444, 2020.
- C. Gu, Z. Huang, X. Chen et al., “TEAD4 promotes tumor development in patients with lung adenocarcinoma via ERK signaling pathway,” Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1866, no. 12, article 165921, 2020.
- P. Langfelder and S. Horvath, “WGCNA: an R package for weighted correlation network analysis,” BMC Bioinformatics, vol. 9, no. 1, p. 559, 2008.
- G. Yu, L. G. Wang, Y. Han, and Q. Y. He, “clusterProfiler: an R package for comparing biological themes among gene clusters,” OMICS, vol. 16, no. 5, pp. 284–287, 2012.
- C. Gu, X. Shi, X. Dang et al., “Identification of common genes and pathways in eight fibrosis diseases,” Frontiers in Genetics, vol. 11, article 627396, 2020.
- Y. Tian, T. J. Morris, A. P. Webster et al., “ChAMP: updated methylation analysis pipeline for Illumina BeadChips,” Bioinformatics, vol. 33, no. 24, pp. 3982–3984, 2017.
- S. Liang, X. Shi, C. Yu et al., “Identification of novel candidate genes in heterotaxy syndrome patients with congenital heart diseases by whole exome sequencing,” Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1866, no. 12, article 165906, 2020.
- X. Shi, T. Huang, J. Wang et al., “Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection,” eBioMedicine, vol. 38, pp. 217–227, 2018.
- X. Shi, L. Cheng, X. T. Jiao et al., “Rare copy number variants identify novel genes in sporadic total anomalous pulmonary vein connection,” Frontiers in Genetics, vol. 9, p. 559, 2018.
- L. Zhang, X. Shi, C. Gu et al., “Identification of cell-to-cell interactions by ligand-receptor pairs in human fetal heart,” Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1866, no. 12, p. 165917, 2020.
- G. Bindea, B. Mlecnik, M. Tosolini et al., “Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer,” Immunity, vol. 39, no. 4, pp. 782–795, 2013.
- B. Yang, E. L. Norton, T. Shih et al., “Late outcomes of strategic arch resection in acute type A aortic dissection,” The Journal of Thoracic and Cardiovascular Surgery, vol. 157, no. 4, pp. 1313–1321.e2, 2019, e2.
- Y. H. Shen and S. A. LeMaire, “Molecular pathogenesis of genetic and sporadic aortic aneurysms and dissections,” Current Problems in Surgery, vol. 54, no. 3, pp. 95–155, 2017.
- J. Ye, Y. Wang, Z. Wang et al., “Circulating Th1, Th2, Th9, Th17, Th22, and Treg levels in aortic dissection patients,” Mediators of Inflammation, vol. 2018, Article ID 5697149, 10 pages, 2018.
- D. Wu, J. C. Choi, A. Sameri et al., “Inflammatory cell infiltrates in acute and chronic thoracic aortic dissection,” Aorta, vol. 1, no. 6, pp. 259–267, 2013.
- R. He, D. C. Guo, A. L. Estrera et al., “Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissections,” The Journal of Thoracic and Cardiovascular Surgery, vol. 131, no. 3, pp. 671–678.e2, 2006.
- K. Suzuki, N. Kimura, M. Mieno et al., “Factors related to white blood cell elevation in acute type A aortic dissection,” PLoS One, vol. 15, no. 2, article e0228954, 2020.
- M. Ma, J. Shi, X. Feng, J. Wang, L. Liu, and X. Wei, “The elevated admission white blood cell count relates to adverse surgical outcome of acute Stanford type A aortic dissection,” Journal of Cardiothoracic Surgery, vol. 15, no. 1, p. 48, 2020.
- X. Z. Duan, Z. Y. Xu, F. L. Lu et al., “Inflammation is related to preoperative hypoxemia in patients with acute Stanford type A aortic dissection,” Journal of Thoracic Disease, vol. 10, no. 3, pp. 1628–1634, 2018.
- L. Han, L. Dai, Y. F. Zhao et al., “CD40L promotes development of acute aortic dissection via induction of inflammation and impairment of endothelial cell function,” Aging (Albany NY), vol. 10, no. 3, pp. 371–385, 2018.
- E. Sbarouni, P. Georgiadou, A. Analitis, and V. Voudris, “High neutrophil to lymphocyte ratio in type A acute aortic dissection facilitates diagnosis and predicts worse outcome,” Expert Review of Molecular Diagnostics, vol. 15, no. 7, pp. 965–970, 2015.
- Z. Wu, Z. Wang, H. Wu et al., “Obesity is a risk factor for preoperative hypoxemia in Stanford A acute aortic dissection,” Medicine (Baltimore), vol. 99, no. 11, article e19186, 2020.
- S. P. Colgan and C. T. Taylor, “Hypoxia: an alarm signal during intestinal inflammation,” Nature Reviews. Gastroenterology & Hepatology, vol. 7, no. 5, pp. 281–287, 2010.
- B. T. Weis-Müller, O. Modlich, I. Drobinskaya et al., “Gene expression in acute Stanford type A dissection: a comparative microarray study,” Journal of Translational Medicine, vol. 4, no. 1, p. 29, 2006.
- J. Feng, S. Ge, L. Zhang, H. Che, and C. Liang, “Aortic dissection is associated with reduced polycystin-1 expression, an abnormality that leads to increased ERK phosphorylation in vascular smooth muscle cells,” European Journal of Histochemistry, vol. 60, no. 4, p. 2711, 2016.
- Y. L. Huang, C. Y. Liang, D. Ritz et al., “Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis,” eLife, vol. 9, 2020.
- J. Yu, C. Zhang, Q. Yu, H. Yu, and B. Zhang, “ADAR1 p110 enhances adhesion of tumor cells to extracellular matrix in hepatocellular carcinoma via up-regulating ITGA2 expression,” Medical Science Monitor, vol. 25, pp. 1469–1479, 2019.
- A. Tsamis, J. T. Krawiec, and D. A. Vorp, “Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review,” J R Soc Interface, vol. 10, no. 83, p. 20121004, 2013.
- L. Xing, Y. Xue, Y. Yang et al., “TMT-based quantitative proteomic analysis identification of integrin alpha 3 and integrin alpha 5 as novel biomarkers in pathogenesis of acute aortic dissection,” BioMed Research International, vol. 2020, Article ID 1068402, 12 pages, 2020.
- X. Yue, X. Yang, X. Lin et al., “Rnd3 haploinsufficient mice are predisposed to hemodynamic stress and develop apoptotic cardiomyopathy with heart failure,” Cell Death & Disease, vol. 5, no. 6, article e1284, 2014.
- P. Chiarugi and E. Giannoni, “Anoikis: a necessary death program for anchorage-dependent cells,” Biochemical Pharmacology, vol. 76, no. 11, pp. 1352–1364, 2008.
- W. Jie, K. C. Andrade, X. Lin, X. Yang, X. Yue, and J. Chang, “Pathophysiological functions of Rnd3/RhoE,” Comprehensive Physiology, vol. 6, no. 1, pp. 169–186, 2015.
- S. Durdu, G. C. Deniz, D. Balci et al., “Apoptotic vascular smooth muscle cell depletion via BCL2 family of proteins in human ascending aortic aneurysm and dissection,” Cardiovascular Therapeutics, vol. 30, no. 6, 316 pages, 2012.
- H. Wang, R. Gu, F. Tian et al., “PHLPP2 as a novel metastatic and prognostic biomarker in non-small cell lung cancer patients,” Thoracic cancer, vol. 10, no. 11, pp. 2124–2132, 2019.
- S. T. Yeh, C. M. Zambrano, W. J. Koch, and N. H. Purcell, “PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulates G-protein-coupled receptor kinase 5 (GRK5)-induced cardiac hypertrophy in vitro,” The Journal of Biological Chemistry, vol. 293, no. 21, pp. 8056–8064, 2018.
Copyright © 2021 Rui Lian et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.