Identification and Analysis of Differentially Expressed Genes Associated with Ferroptosis and HIV in PASMCs Based on Bioinformatics


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Abstract

Background:HIV-associated pulmonary arterial hypertension (HIV-PAH), a rare and fatal condition within the pulmonary arterial hypertension spectrum, is linked to HIV infection. While ferroptosis, an iron-dependent cell death form, is implicated in various lung diseases, its role in HIVPAH development remains unclear.

Methods:Leveraging Gene Expression Omnibus data, we identified differentially expressed genes (DEGs) in pulmonary arterial smooth muscle cells, including HIV-related DEGs (HIV-DEGs) and ferroptosis-related HIV-DEGs (FR-HIV-DEGs). PPI network analysis of FR-HIV-DEGs using CytoHubba in Cytoscape identified hub genes. We conducted functional and pathway enrichment analyses for FR-HIV-DEGs, HIV-DEGs, and hub genes. Diagnostic value assessment of hub genes utilized ROC curve analysis. Key genes were further screened, and external validation was performed. Additionally, we predicted a potential ceRNA regulatory network for key genes.

Results:1372 DEGs were found, of which 228 were HIV-DEGs, and 20 were FR-HIV-DEGs. TP53, IL6, PTGS2, IL1B (downregulated), and PPARG (upregulated) were the five hub genes that were screened. TP53, IL6, and IL1B act as ferroptosis drivers, PTGS2 as a ferroptosis marker, and PPARG as a ferroptosis inhibitor. Enrichment analysis indicated biological processes enriched in \"response to oxidative stress\" and pathways enriched in \"human cytomegalovirus infection.\" Key genes IL6 and PTGS2 exhibited strong predictive value via ROC curve analysis and external validation. The predicted ceRNA regulatory network identified miRNAs (has-mir-335-5p, has-mir-124-3p) targeting key genes and lncRNAs (XIST, NEAT1) targeting these miRNAs.

Conclusion:This study advances our understanding of potential mechanisms in HIV-PAH pathogenesis, emphasizing the involvement of ferroptosis. The findings offer valuable insights for future research in HIV-PAH.

About the authors

Tong Lu

College of Medical Technology, Qiqihar Medical University

Email: info@benthamscience.net

Linna Guo

Department of Anatomy, Qiqihar Medical University

Email: info@benthamscience.net

Yong Ma

Department of Anatomy, Qiqihar Medical University

Email: info@benthamscience.net

Lijie Yao

Department of Anatomy, Qiqihar Medical University

Email: info@benthamscience.net

Li Li

Department of Anatomy, Qiqihar Medical University

Email: info@benthamscience.net

Wenshan Bian

Department of Anatomy, Qiqihar Medical University

Email: info@benthamscience.net

Miao Xiu

Department of Anatomy, Qiqihar Medical University

Email: info@benthamscience.net

Yang Jiang

Department of Anatomy, Qiqihar Medical University

Author for correspondence.
Email: info@benthamscience.net

Yongtao Li

Department of Anatomy, Qiqihar Medical University

Author for correspondence.
Email: info@benthamscience.net

Haifeng Jin

Department of Anatomy, Qiqihar Medical University

Author for correspondence.
Email: info@benthamscience.net

References

  1. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2022; 43(38): 3618-731.
  2. Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension. JAMA 2022; 327(14): 1379-91. doi: 10.1001/jama.2022.4402 PMID: 35412560
  3. Cicalini S, Chinello P, Grilli E, Petrosillo N. Treatment and outcome of pulmonary arterial hypertension in HIV-infected patients: A review of the literature. Curr HIV Res 2009; 7(6): 589-96. doi: 10.2174/157016209789973583 PMID: 19929793
  4. Palakeel JJ, Ali M, Chaduvula P, et al. An outlook on the etiopathogenesis of pulmonary hypertension in HIV. Cureus 2022; 14(7): e27390. doi: 10.7759/cureus.27390 PMID: 36046315
  5. Henriques-Forsythe M, Annangi S, Farber HW. Prevalence and hospital discharge status of human immunodeficiency virus-associated pulmonary arterial hypertension in the United States. Pulm Circ 2015; 5(3): 506-12. doi: 10.1086/682222 PMID: 26401251
  6. Jarrett H, Barnett C. HIV-associated pulmonary hypertension. Curr Opin HIV AIDS 2017; 12(6): 566-71. doi: 10.1097/COH.0000000000000418 PMID: 28902721
  7. Dhillon NK, Li F, Xue B, et al. Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction. Am J Respir Cell Mol Biol 2011; 45(1): 40-52. doi: 10.1165/rcmb.2010-0097OC PMID: 20802087
  8. Jin H, Jiao Y, Guo L, et al. Astragaloside IV blocks monocrotaline induced pulmonary arterial hypertension by improving inflammation and pulmonary artery remodeling. Int J Mol Med 2020; 47(2): 595-606. doi: 10.3892/ijmm.2020.4813 PMID: 33416126
  9. Guo ML, Kook YH, Shannon CE, Buch S. Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH. Cell Death Discov 2018; 4(1): 85. doi: 10.1038/s41420-018-0087-9 PMID: 30109141
  10. Mou Y, Wang J, Wu J, et al. Ferroptosis, a new form of cell death: Opportunities and challenges in cancer. J Hematol Oncol 2019; 12(1): 34. doi: 10.1186/s13045-019-0720-y PMID: 30925886
  11. Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22(4): 266-82. doi: 10.1038/s41580-020-00324-8 PMID: 33495651
  12. Li S, Zhang X. Iron in cardiovascular disease: Challenges and potentials. Front Cardiovasc Med 2021; 8: 707138. doi: 10.3389/fcvm.2021.707138 PMID: 34917655
  13. Ren JX, Sun X, Yan XL, Guo ZN, Yang Y. Ferroptosis in neurological diseases. Front Cell Neurosci 2020; 14: 218. doi: 10.3389/fncel.2020.00218 PMID: 32754017
  14. Li Y, Yang Y, Yang Y. Multifaceted roles of ferroptosis in lung diseases. Front Mol Biosci 2022; 9: 919187. doi: 10.3389/fmolb.2022.919187 PMID: 35813823
  15. Ruiter G, Lankhorst S, Boonstra A, et al. Iron deficiency is common in idiopathic pulmonary arterial hypertension. Eur Respir J 2011; 37(6): 1386-91. doi: 10.1183/09031936.00100510 PMID: 20884742
  16. Rhodes CJ, Howard LS, Busbridge M, et al. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: Clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol 2011; 58(3): 300-9. doi: 10.1016/j.jacc.2011.02.057 PMID: 21737024
  17. Cribbs SK, Crothers K, Morris A. Pathogenesis of HIV-related lung disease: Immunity, infection, and inflammation. Physiol Rev 2020; 100(2): 603-32. doi: 10.1152/physrev.00039.2018 PMID: 31600121
  18. Basyal B, Jarrett H, Barnett CF. Pulmonary hypertension in HIV. Can J Cardiol 2019; 35(3): 288-98. doi: 10.1016/j.cjca.2019.01.005 PMID: 30825951
  19. Zhu W, Liu S. The role of human cytomegalovirus in atherosclerosis: A systematic review. Acta Biochim Biophys Sin (Shanghai) 2020; 52(4): 339-53. doi: 10.1093/abbs/gmaa005 PMID: 32253424
  20. Monk CH, Zwezdaryk KJ. Host mitochondrial requirements of cytomegalovirus replication. Curr Clin Microbiol Rep 2020; 7(4): 115-23. doi: 10.1007/s40588-020-00153-5 PMID: 33816061
  21. Fulkerson HL, Nogalski MT, Collins-McMillen D, Yurochko AD. Overview of human cytomegalovirus pathogenesis. Methods Mol Biol 2021; 2244: 1-18. doi: 10.1007/978-1-0716-1111-1_1 PMID: 33555579
  22. Smith FB, Arias JH, Elmquist TH, Mazzara JT. Microvascular cytomegalovirus endothelialitis of the lung: A possible cause of secondary pulmonary hypertension in a patient with AIDS. Chest 1998; 114(1): 337-40. doi: 10.1378/chest.114.1.337 PMID: 9674494
  23. Walter-Nicolet E, Leblanc M, Leruez-Ville M, Hubert P, Mitanchez D. Congenital cytomegalovirus infection manifesting as neonatal persistent pulmonary hypertension: Report of two cases. Pulm Med 2011; 2011: 1-4. doi: 10.1155/2011/293285 PMID: 21766016
  24. Manzoni P, Vivalda M, Mostert M, et al. CMV infection associated with severe lung involvement and persistent pulmonary hypertension of the newborn (PPHN) in two preterm twin neonates. Early Hum Dev 2014; 90 (Suppl. 2): S25-7. doi: 10.1016/S0378-3782(14)50008-4 PMID: 25220122
  25. Pham A, El Mjati H, Nathan N, Kieffer F, Mitanchez D. Congenital cytomegalovirus infection manifesting as neonatal respiratory distress in an HIV-exposed uninfected newborn. Arch Pediatr 2017; 24(9): 872-6.
  26. Matura LA, Ventetuolo CE, Palevsky HI, et al. Interleukin-6 and tumor necrosis factor-α are associated with quality of life-related symptoms in pulmonary arterial hypertension. Ann Am Thorac Soc 2015; 12(3): 370-5. doi: 10.1513/AnnalsATS.201410-463OC PMID: 25615959
  27. Tcherakian C, Rivaud E, Catherinot E, Zucman D, Metivier AC, Couderc LJ. Pulmonary arterial hypertension related to HIV: Is inflammation related to IL-6 the cornerstone? Rev Pneumol Clin 2011; 67(4): 250-7. doi: 10.1016/j.pneumo.2011.06.006 PMID: 21920286
  28. Alqarni AA, Brand OJ, Pasini A, Alahmari M, Alghamdi A, Pang L. Imbalanced prostanoid release mediates cigarette smoke-induced human pulmonary artery cell proliferation. Respir Res 2022; 23(1): 136. doi: 10.1186/s12931-022-02056-z PMID: 35643499
  29. Fredenburgh LE, Liang OD, Macias AA, et al. Absence of cyclooxygenase-2 exacerbates hypoxia-induced pulmonary hypertension and enhances contractility of vascular smooth muscle cells. Circulation 2008; 117(16): 2114-22. doi: 10.1161/CIRCULATIONAHA.107.716241 PMID: 18391113
  30. Durmus S, Atahan E, Avci Kilickiran B, et al. Significance of Cyclooxgenase-2 gene polymorphism and related miRNAs in pulmonary arterial hypertension. Clin Biochem 2022; 107: 33-9. doi: 10.1016/j.clinbiochem.2022.06.001 PMID: 35724768
  31. Ng L. The role of thiamine in HIV infection. Int J Infect Dis 2013; 17(4): e221-7.
  32. Samikkannu T, Rao KVK, Ding H, et al. Immunopathogenesis of HIV infection in cocaine users: Role of arachidonic acid. PLoS One 2014; 9(8): e106348. doi: 10.1371/journal.pone.0106348 PMID: 25171226
  33. Chinniah R, Adimulam T, Nandlal L, Arumugam T, Ramsuran V. The effect of miRNA gene regulation on HIV disease. Front Genet 2022; 13: 862642. doi: 10.3389/fgene.2022.862642 PMID: 35601502
  34. Shen L, Wu C, Zhang J, et al. Roles and potential applications of lncRNAs in HIV infection. Int J Infect Dis 2020; 92: 97-104.
  35. Wang D, Xu H, Wu B, et al. Long non coding RNA MALAT1 sponges miR 124 3p.1/KLF5 to promote pulmonary vascular remodeling and cell cycle progression of pulmonary artery hypertension. Int J Mol Med 2019; 44(3): 871-84. doi: 10.3892/ijmm.2019.4256 PMID: 31257528
  36. Wu L, Tian X, Zuo H, et al. miR-124-3p delivered by exosomes from heme oxygenase-1 modified bone marrow mesenchymal stem cells inhibits ferroptosis to attenuate ischemia–reperfusion injury in steatotic grafts. J Nanobiotechnology 2022; 20(1): 196. doi: 10.1186/s12951-022-01407-8 PMID: 35459211
  37. Ma H, Ye P, Zhang A, Yu W, Lin S, Zheng Y. Upregulation of miR-335-5p contributes to right ventricular remodeling via calumenin in pulmonary arterial hypertension. BioMed Res Int 2022; 2022: 1-16. doi: 10.1155/2022/9294148 PMID: 36246958
  38. Cheng X, Wang Y, Liu L, Lv C, Liu C, Xu J. SLC7A11, a potential therapeutic target through induced ferroptosis in colon adenocarcinoma. Front Mol Biosci 2022; 9: 889688. doi: 10.3389/fmolb.2022.889688 PMID: 35517862
  39. Qin S, Predescu D, Carman B, et al. Up-regulation of the long noncoding RNA x-inactive–specific transcript and the sex bias in pulmonary arterial hypertension. Am J Pathol 2021; 191(6): 1135-50. doi: 10.1016/j.ajpath.2021.03.009 PMID: 33836164
  40. Pinto DO, Scott TA, DeMarino C, et al. Effect of transcription inhibition and generation of suppressive viral non-coding RNAs. Retrovirology 2019; 16(1): 13. doi: 10.1186/s12977-019-0475-0 PMID: 31036006
  41. Dou X, Ma Y, Qin Y, et al. NEAT1 silencing alleviates pulmonary arterial smooth muscle cell migration and proliferation under hypoxia through regulation of miR 34a 5p/KLF4 in vitro. Mol Med Rep 2021; 24(5): 749. doi: 10.3892/mmr.2021.12389 PMID: 34468014
  42. Zhang Y, Luo M, Cui X, O’Connell D, Yang Y. Long noncoding RNA NEAT1 promotes ferroptosis by modulating the miR-362-3p/MIOX axis as a ceRNA. Cell Death Differ 2022; 29(9): 1850-63. doi: 10.1038/s41418-022-00970-9 PMID: 35338333
  43. Shadrina OA, Kikhay TF, Agapkina YY, Gottikh MB. SFPQ and NONO proteins and long non-coding NEAT1 RNA: Cellular functions and role in the HIV-1 life cycle. Mol Biol 2022; 56(2): 259-74. PMID: 35403619
  44. Duyne RV, Narayanan A. K-Hall K, Saifuddin M, Shultz L, Kashanchi F. Humanized mouse models of HIV-1 latency. Curr HIV Res 2011; 9(8): 595-605. doi: 10.2174/157016211798998781 PMID: 22211664
  45. Rodriguez-Irizarry VJ, Schneider AC, Ahle D, et al. Mice with humanized immune system as novel models to study HIV-associated pulmonary hypertension. Front Immunol 2022; 13: 936164. doi: 10.3389/fimmu.2022.936164 PMID: 35990658

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