https://orcid.org/0000-0002-1017-4341
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Abstract
Introduction
Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD), which can worsen the prognosis and increase the mortality of COPD patients. Circular RNA (circRNA) has been discovered to participate in the occurrence and progression of PH in COPD and may have significant prospects for advanced diagnostics and prognosis evaluation. However, the expression profile of circRNAs in human lung tissues with definite diagnosis of COPD-PH remains to be further explored and validated.
Methods
Twelve human lung tissue samples (6 each from COPD-PH and control groups) were collected and subjected to high-throughput sequencing. QRT-PCR was performed to validate the differential expression levels of the top 10 dysregulated circRNAs in patients’ plasma samples, HPAECs and HPASMCs. Functional and pathway enrichment analysis on target genes was performed to explore the potential functions and pathways of those circRNAs. Hub genes obtained after conducting bioinformatics analysis on the predicted target mRNAs were verified by qRT-PCR in HPAECs and HPASMCs, and then we selected VCAN as a potential key gene involved in the pathogenesis of COPD-PH for immunohistochemistry validation in lung tissue.
Results
A total of 136 circRNAs (39 up-regulated and 97 down-regulated) were differentially expressed between the two groups. Following qRT-PCR validation, two circRNAs (hsa_circ_0007608 and hsa_circ_0064656) were believed to be involved in the pathogenesis. GO and KEGG pathway analysis suggested that these two DECs were mainly related to the celluar proliferation, migration and EndMT. PPI network revealed 11 pairs of key mRNAs. VCAM1, VCAN and THBS1, three hub mRNAs with the highest reliability among all, were validated and proven to be up-regulated in COPD-PH. We innovatively found that VCAN may be involved in COPD-PH.
Conclusion
This study identified the functional circRNAs, providing insights into the molecular mechanisms and predictions of COPD-PH, and may provide potential diagnostic biomarkers or therapeutic targets for COPD-PH.
Data Sharing Statement
All data generated or analyzed during this study are included in this published article and its Supplementary Information File. The datasets generated or analysed during the current study are available in the Sequence Read Archive (SRA) database of NCBI [https://www.ncbi.nlm.nih.gov/sra/PRJNA913650].
Ethics Approval Statement
All donated lung tissue originates from patients underwent lung nodules or lung transplantation at Wuxi People’s Hospital Affiliated to Nanjing Medical University, and all experimental work was approved by the ethical review board of Wuxi People’s Hospital Affiliated to Nanjing Medical University. We confirm that lung donations were conducted with the full informed consent of the donor or their next-of-kin if deceased. This study was conducted in accordance with the tenets of the Declaration of Helsinki. The procedures were approved by the Ethics Committee of Nanjing Medical University (KY21033).
Author Contributions
All authors made a significant contribution to the work reported, whether in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all of these areas. All authors took part in drafting, revising or critically reviewing the article, gave final approval of the version to be published, have agreed on the journal to which the article has been submitted and agreed to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no competing interests in this work.