Identification and Validation of Vascular-Associated Biomarkers for the Prognosis and Potential Pathogenesis of Hypertension Using Comprehensive Bioinformatics Methods
Background: Hypertension, also
known as increased blood pressure, is a phenomenon in which blood flows in
blood vessels and causes persistently higher-than-normal pressure on the vessel
wall. The identification of novel prognostic and pathogenesis biomarkers plays
a key role in the management of hypertension. Methods: The GSE7483 and
GSE75815 datasets from the gene expression omnibus (GEO) database were used to
identify the genes associated with hypertension that were differentially
expressed genes (DEGs). The functional role of the DEGs was elucidated by gene
body (GO) enrichment analysis. In addition, we performed an immune infiltration
assay and GSEA on the DEGs of hypertensive patients and verified the expression
of novel DEGs in the blood of hypertensive patients by RT-qPCR. Results: A total of 267 DEGs were identified from the GEO database. GO analysis revealed
that these genes were associated mainly with biological processes such as
fibroblast proliferation, cell structural organization, extracellular matrix
organization, vasculature development regulation, and angiogenesis. We
identified five possible biomarkers, Ecm1, Sparc, Sphk1, Thbsl, and Mecp2,
which correlate with vascular development and angiogenesis characteristic of hypertension by bioinformatics, and
explored the clinical expression levels ofthese genes by RT-qPCR, and found that Sparc, Sphk1, and Thbs1 showed
significant up-regulation, in agreement with the results of the bioinformatics
analysis. Conclusion: Our study suggested that Sparc, Sphk1 and Thbs1
may be potential novel biomarkers for the diagnosis, treatment and prognosis of
hypertension and that they are involved in the regulation of vascular
development and angiogenesis in hypertension.
References
[1]
Liu, Y., Kong, X., Jiang, Y., et al. (2022) Association of AGTR1 A1166C and CYP2C9*3 Gene Polymorphisms with the Antihypertensive Effect of Valsartan. International Journal of Hypertension, 2022, Article ID: 7677252.
https://doi.org/10.1155/2022/7677252
[2]
Kjeldsen, S. (2018) Hypertension and Cardiovascular Risk: General Aspects. Pharmacological Research, 129, 95-99. https://doi.org/10.1016/j.phrs.2017.11.003
[3]
Lim, S., Lee, K., Han, T., et al. (2024) Antihypertensive Effect of Milk Fermented by Lactiplantibacillus plantarum K79 on Spontaneously Hypertensive Rats. Food Science of Animal Resources, 44, 178-188. https://doi.org/10.5851/kosfa.2023.e70
[4]
World Health Organization (2021) WHO Guidelines Approved by the Guidelines Review Committee. Guideline for the Pharmacological Treatment of Hypertension in Adults. Geneva.
[5]
Kim, B., Lee, Y., Shin, J., et al. (2024) Blood Pressure and Variability Responses to the Downtitration of Antihypertensive Drugs. Journal of Hypertension.
https://doi.org/10.1097/HJH.0000000000003668
[6]
Wang, Z., Liu, Y., Liu, J., et al. (2011) HSG/Mfn2 Gene Polymorphism and Essential Hypertension: A Case-Control Association Study in Chinese. Journal of Atherosclerosis and Thrombosis, 18, 24-31. https://doi.org/10.5551/jat.5611
[7]
Holtstrater, C., Schrors, B., Bukur, T. and Lower, M. (2020) Bioinformatics for Cancer Immunotherapy. In: Boegel, S., Ed., Bioinformatics for Cancer Immunotherapy, Humana, New York, 1-9. https://doi.org/10.1007/978-1-0716-0327-7_1
[8]
Ye, F., Huang, W. and Guo, G. (2017) Studying Hematopoiesis Using Single-Cell Technologies. Journal of Hematology & Oncology, 10, Article No. 27.
https://doi.org/10.1186/s13045-017-0401-7
[9]
Treppner, M., Salas-Bastos, A., Hess, M., et al. (2021) Synthetic Single Cell RNA Sequencing Data from Small Pilot Studies Using Deep Generative Models. Scientific Reports, 11, Article No. 9403. https://doi.org/10.1038/s41598-021-88875-4
[10]
Li, D., Hao, X. and Song, Y. (2018) Identification of the Key MicroRNAs and the MiRNA-MRNA Regulatory Pathways in Prostate Cancer by Bioinformatics Methods. BioMed Research International, 2018, Article ID: 6204128.
https://doi.org/10.1155/2018/6204128
[11]
Zhu, Y., Yang, X. and Zu, Y. (2022) Integrated Analysis of WGCNA and Machine Learning Identified Diagnostic Biomarkers in Dilated Cardiomyopathy with Heart Failure. Frontiers in Cell and Developmental Biology, 10, Article 1089915.
https://doi.org/10.3389/fcell.2022.1089915
[12]
Guo, Q. (2023) Bioinformatics Analysis of the Diversity of Gut Microbiota and Different Microbiota on Insulin Resistance in Diabetes Mellitus Patients. Heliyon, 9, e22117. https://doi.org/10.1016/j.heliyon.2023.e22117
[13]
Tian, Y., Yang, J., Lan, M., et al. (2020) Construction and Analysis of a Joint Diagnosis Model of Random Forest and Artificial Neural Network for Heart Failure. Aging, 12, 26221-26235. https://doi.org/10.18632/aging.202405
[14]
Cleaver, O. (2021) Mouse Models of Vascular Development and Disease. Current Opinion in Hematology, 28, 179-188.
https://doi.org/10.1097/MOH.0000000000000649
[15]
Ahir, B., Engelhard, H. and Lakka, S. (2020) Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma. Molecular Neurobiology, 57, 2461-2478.
https://doi.org/10.1007/s12035-020-01892-8
[16]
Langen, U., Ayloo, S. and Gu, C. (2019) Development and Cell Biology of the Blood-Brain Barrier. Annual Review of Cell and Developmental Biology, 35, 591-613.
https://doi.org/10.1146/annurev-cellbio-100617-062608
[17]
Patel, S., Nilsson, M., Le, X., et al. (2023) Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy. Clinical Cancer Research, 29, 30-39.
https://doi.org/10.1158/1078-0432.CCR-22-1366
[18]
Hicklin, D. and Ellis, L. (2005) Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis. Journal of Clinical Oncology, 23, 1011-1027.
https://doi.org/10.1200/JCO.2005.06.081
[19]
Pasqua, T., Pagliaro, P., Rocca, C., et al. (2018) Role of NLRP-3 Inflammasome in Hypertension: A Potential Therapeutic Target. Current Pharmaceutical Biotechnology, 19, 708-714. https://doi.org/10.2174/1389201019666180808162011
[20]
Flammer, A., Anderson, T., Celermajer, D., et al. (2012) The Assessment of Endothelial Function: From Research Into Clinical Practice. Circulation, 126, 753-767.
https://doi.org/10.1161/CIRCULATIONAHA.112.093245
[21]
Touyz, R., Alves-Lopes, R., Rios, F., et al. (2018) Vascular Smooth Muscle Contraction in Hypertension. Cardiovascular Research, 114, 529-539.
https://doi.org/10.1093/cvr/cvy023
[22]
Pyne, N.J. and Pyne, S. (2020) Recent Advances in the Role of Sphingosine 1-Phosphate in Cancer. FEBS Letters, 594, 3583-3601.
https://doi.org/10.1002/1873-3468.13933
[23]
Mcginley, M.P. and Cohen, J.A. (2021) Sphingosine 1-Phosphate Receptor Modulators in Multiple Sclerosis and Other Conditions. The Lancet, 398, 1184-1194.
https://doi.org/10.1016/S0140-6736(21)00244-0
[24]
Obinata, H. and Hla, T. (2019) Sphingosine 1-Phosphate and Inflammation. International Immunology, 31, 617-625. https://doi.org/10.1093/intimm/dxz037
[25]
Schneider, G. (2020) S1P Signaling in the Tumor Microenvironment. Advances in Experimental Medicine and Biology, 1223, 129-153.
https://doi.org/10.1007/978-3-030-35582-1_7
[26]
Wang, Y., Wu, H., Deng, R., et al. (2021) Geniposide Downregulates the VEGF/SphK1/S1P Pathway and Alleviates Angiogenesis in Rheumatoid Arthritis in Vivo and in Vitro. Phytotherapy Research, 35, 4347-4362.
https://doi.org/10.1002/ptr.7130
[27]
Sharma, K., Chanana, N., Mohammad, G., et al. (2021) Hypertensive Patients Exhibit Enhanced Thrombospondin-1 Levels at High-Altitude. Life, 11, Article 893.
https://doi.org/10.3390/life11090893
[28]
Kuebler, W.M. (2017) What Mediates the Effects of Thrombospondin-1 in Pulmonary Hypertension? New Evidence for a Dual-Pronged Role of CD47. Cardiovascular Research, 113, 3-5. https://doi.org/10.1093/cvr/cvw232
[29]
Zhong, C., Si, Y., Yang, H., et al. (2023) Identification of Monocyte-Associated Pathways Participated in the Pathogenesis of Pulmonary Arterial Hypertension Based on Omics-Data. Pulmonary Circulation, 13, e12319.
https://doi.org/10.1002/pul2.12319
[30]
Carnevale, L., Perrotta, M., Mastroiacovo, F., et al. (2024) Advanced Magnetic Resonance Imaging (MRI) to Define the Microvascular Injury Driven by Neuroinflammation in the Brain of a Mouse Model of Hypertension. Hypertension, 81, 636-647. https://doi.org/10.1161/HYPERTENSIONAHA.123.21940
[31]
Rodriguez-Iturbe, B., Pons, H. and Johnson, R. (2017) Role of the Immune System in Hypertension. Physiological Reviews, 97, 1127-1164.
https://doi.org/10.1152/physrev.00031.2016
[32]
Ferreira, N., Tostes, R., Paradis, P., et al. (2021) Aldosterone, Inflammation, Immune System, and Hypertension. American Journal of Hypertension, 34, 15-27.
https://doi.org/10.1093/ajh/hpaa137
[33]
Gan, L., Ye, D., Feng, Y., et al. (2023) Immune Cells and Hypertension. Immunologic Research, 72, 1-13. https://doi.org/10.1007/s12026-023-09414-z
[34]
Mei, Y., Thompson, M., Cohen, R., et al. (2015) Autophagy and Oxidative Stress in Cardiovascular Diseases. Biochimica et Biophysica Acta, 1852, 243-251.
https://doi.org/10.1016/j.bbadis.2014.05.005
[35]
Mao, M., Song, S., Li, X., et al. (2023) Advances in Epigenetic Modifications of Autophagic Process in Pulmonary Hypertension. Frontiers in Immunology, 14, Article 1206406. https://doi.org/10.3389/fimmu.2023.1206406
