Specific Genes and microRNAs as Novel Diagnostic Biomarkers for the Potential Progression of Pulmonary Arterial Hypertension
Abstract
Background: Pulmonary arterial hypertension (PAH) is characterized by high blood pressure in the lungs due to obstruction of small pulmonary arteries. Its exact cause is unknown. We aimed to identify specific genes, signaling pathways, and microRNAs (miRNAs) as novel diagnostic biomarkers for PAH progression.
Methods: We analyzed differentially expressed genes (DEGs) from PAH and control samples in the GSE144932 and GSE131793 datasets using GEO2R. We performed GO enrichment and KEGG pathway analyses. miRNAs targeting common DEGs were identified using miRDB and TargetScan.
Results: MYLK and CLU were upregulated in both datasets, implicating calcium signaling and coagulation pathways, respectively. In silico analysis showed that miR-9-5p, miR-3179, and miR-580-3p potentially target MYLK; miR-369-3p potentially targets CLU; and miR-499a-5p potentially targets both.
Conclusion: This study identifies MYLK and CLU, and their associated miRNAs (miR-9-5p, miR-3179, miR-580-3p, miR-499a-5p, and miR-369-3p), as potential noninvasive diagnostic biomarkers for PAH, requiring experimental validation.
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22. Liu X, Meng L, Li J, et al (2015). Secretory clusterin is upregulated in rats with pulmonary arterial hypertension induced by systemic-to-pulmonary shunts and exerts important roles in pulmonary artery smooth muscle cells. Acta Physiol (Oxf), 213(2): 505-18.
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24. Zhou G, Chen T, Raj JU (2015). MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol, 52(2): 139-51.
25. Xiao Y, Zhang Y, Chen Y, et al (2019). Inhibition of MicroRNA-9-5p Protects Against Cardiac Remodeling Following Myocardial Infarction in Mice. Hum Gene Ther, 30(3): 286-301.
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27. Lago-Docampo M, Iglesias-López A, Vilariño C, et al (2024). Overexpression of miR-3168 impairs angiogenesis in Pulmonary Arterial Hypertension: Insights from circulating miRNA analysis. medRxiv, 1: 2024-04.
28. Adyshev DM, Moldobaeva N, Mapes B, et al (2013). MicroRNA regulation of nonmuscle myosin light chain kinase expression in human lung endothelium. Am J Respir Cell Mol Biol, 49(1): 58-66.
29. Galleggiante V, De Santis S, Liso M, et al (2019). Quercetin-Induced miR-369-3p Suppresses Chronic Inflammatory Response Targeting C/EBP-β. Mol Nutr Food Res, 63(19): e1801390.
30. Scalavino V, Liso M, Cavalcanti E, et al (2020). miR-369-3p modulates inducible nitric oxide synthase and is involved in regulation of chronic inflammatory response. Scie Rep, 10(1): 15942.
31. Su T, Gu C, Draga D, et al (2021). Integrative analysis of miRNA-mRNA network in high altitude retinopathy by bioinformatics analysis. Biosci Rep, 41(1): BSR20200776.
32. Iwatani N, Kubota K, Ikeda Y, et al (2021). Different characteristics of mitochondrial dynamics-related miRNAs on the hemodynamics of pulmonary artery hypertension and chronic thromboembolic pulmonary hypertension. J Cardiol, 78(1): 24-30.
2. Sysol J, Machado R, (2018). Classification and pathophysiology of pulmonary hypertension. Continuing Cardiol Educ, 4(1): 2-12.
3. Santos-Gomes J, Gandra I, Adão R., et al (2022). An overview of circulating pulmonary arterial hypertension biomarkers. Front Cardiovasc Med, 9: 924873.
4. Galiè N, McLaughlin VV, Rubin LJ, et al (2019). An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J, 53(1): 1802148.
5. Lau,E.M, Giannoulatou E, Celermajer DS, et al (2017). Epidemiology and treatment of pulmonary arterial hypertension. Nat Rev Cardiol, 14(10): 603-614.
6. Smith BP, Best DH, Elliott CG (2012). Genetics and pharmacogenomics in pulmonary arterial hypertension. Heart Fail Clin, 8(3): 319-330.
7. Lan NS, Massam BD, Kulkarni SS, et al (2018). Pulmonary arterial hypertension: pathophysiology and treatment. Diseases, 6(2): 38.
8. Shah AJ, Vorla M, Kalra DK (2022). Molecular pathways in pulmonary arterial hypertension. Int J Mol Sci, 23(17): 10001.
9. Anwar A, Ruffenach G, Mahajan A, et al (2016). Novel biomarkers for pulmonary arterial hypertension. Respir Res, 17: 88.
10. Group BDW, Atkinson Jr AJ, Colburn WA, et al (2001). Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther, 69(3): 89-95.
11. Hojda SE, Chis IC, Clichici S (2022). Biomarkers in pulmonary arterial hypertension. Diagnostics (Basel), 12(12):3033.
12. Kanwar MK (2020). Biomarkers in pulmonary arterial hypertension: Moving closer toward precision medicine? J Heart Lung Transplant, 39(4): 287-288.
13. Ezenwa C, Soremekun OS, Nashiru O, et al (2020). Identification of differentially expressed genes present in the whole blood of Pulmonary Arterial Hypertension patients and control patients: An integrated bioinformatics approach. Informatics in Medicine Unlocked, 20: 100380.
14. Rajagopal S, Yen-Rei AY (2022). The pathobiology of pulmonary arterial hypertension. Cardiol Clin, 40(1): 1-12.
15. Hong F, Haldeman BD, Jackson D, et al (2011). Biochemistry of smooth muscle myosin light chain kinase. Arch Biochem Biophys, 510(2): 135-146.
16. Lai N, Lu W, Wang J (2015). Ca2+ and ion channels in hypoxia-mediated pulmonary hypertension. Int J Clin Exp Pathol, 8(2): 1081-92.
17. Anis M, Gonzales J, Halstrom R, et al (2022). Non-muscle MLCK contributes to endothelial cell hyper-proliferation through the ERK pathway as a mechanism for vascular remodeling in pulmonary hypertension. Int J Mol Sci, 23(21): 13641.
18. Sitbon O, Humbert M, Jaïs X., et al (2005). Long-term response to Calcium-channel-blocker response in idiopathic pulmonary arterial hypertension. Circulation, 111(23):3105-11.
19. Lai Y, Huang Y (2021). Mechanisms of Mechanical Force Induced Pulmonary Vascular Endothelial Hyperpermeability. Front Physiol, 12: 714064.
20. Koller L, Richter B, Winter MP, et al (2017). Clusterin/apolipoprotein J is independently associated with survival in patients with chronic heart failure. J Clin Lipidol, 11(1): 178-184.
21. Yang N, Qin Q (2015). Apolipoprotein J: A New Predictor and Therapeutic Target in Cardiovascular Disease? Chin Med J (Engl), 128(18): 2530-4.
22. Liu X, Meng L, Li J, et al (2015). Secretory clusterin is upregulated in rats with pulmonary arterial hypertension induced by systemic-to-pulmonary shunts and exerts important roles in pulmonary artery smooth muscle cells. Acta Physiol (Oxf), 213(2): 505-18.
23. Habiel DM, Camelo A, Espindola M, et al (2017). Divergent roles for Clusterin in Lung Injury and Repair. Sci Rep, 7(1): 15444.
24. Zhou G, Chen T, Raj JU (2015). MicroRNAs in pulmonary arterial hypertension. Am J Respir Cell Mol Biol, 52(2): 139-51.
25. Xiao Y, Zhang Y, Chen Y, et al (2019). Inhibition of MicroRNA-9-5p Protects Against Cardiac Remodeling Following Myocardial Infarction in Mice. Hum Gene Ther, 30(3): 286-301.
26. Shan F, Li J, Huang QY (2014). HIF-1 alpha-induced up-regulation of miR-9 contributes to phenotypic modulation in pulmonary artery smooth muscle cells during hypoxia. J Cell Physiol, 229(10): 1511-20.
27. Lago-Docampo M, Iglesias-López A, Vilariño C, et al (2024). Overexpression of miR-3168 impairs angiogenesis in Pulmonary Arterial Hypertension: Insights from circulating miRNA analysis. medRxiv, 1: 2024-04.
28. Adyshev DM, Moldobaeva N, Mapes B, et al (2013). MicroRNA regulation of nonmuscle myosin light chain kinase expression in human lung endothelium. Am J Respir Cell Mol Biol, 49(1): 58-66.
29. Galleggiante V, De Santis S, Liso M, et al (2019). Quercetin-Induced miR-369-3p Suppresses Chronic Inflammatory Response Targeting C/EBP-β. Mol Nutr Food Res, 63(19): e1801390.
30. Scalavino V, Liso M, Cavalcanti E, et al (2020). miR-369-3p modulates inducible nitric oxide synthase and is involved in regulation of chronic inflammatory response. Scie Rep, 10(1): 15942.
31. Su T, Gu C, Draga D, et al (2021). Integrative analysis of miRNA-mRNA network in high altitude retinopathy by bioinformatics analysis. Biosci Rep, 41(1): BSR20200776.
32. Iwatani N, Kubota K, Ikeda Y, et al (2021). Different characteristics of mitochondrial dynamics-related miRNAs on the hemodynamics of pulmonary artery hypertension and chronic thromboembolic pulmonary hypertension. J Cardiol, 78(1): 24-30.
| Files | ||
| Issue | Vol 54 No 12 (2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Pulmonary arterial hypertension Biomarkers Genes MicroRNAs | ||
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How to Cite
1.
Gholipour A, Farsi M, Sari F, Khajali Z, Maleki M, Malakootian M. Specific Genes and microRNAs as Novel Diagnostic Biomarkers for the Potential Progression of Pulmonary Arterial Hypertension. Iran J Public Health. 2025;54(12):2754-2763.
