Abstract
Pulmonary arterial hypertension (PAH) is characterized by abnormal remodeling of pulmonary vessel walls caused by excessive pulmonary arterial smooth muscle cell (PASMC) proliferation. Our previous clinical studies have demonstrated the importance of the downregulated circRNA in PAH. However, the role of upregulated circRNAs is still elusive. Here, we identified the upregulated circRNA in PAH patients, hsa_circWDR37_016 (circWDR37), as a key regulator of hypoxic proliferative disorder of pulmonary arterial smooth muscle cells (PASMCs). Quantitative real-time PCR (qRT-PCR) analysis validated that exposure to hypoxia markedly increased the circWDR37 level in cultured human PASMCs. As evidenced by flow cytometry, 5-ethynyl-2′-deoxyuridine (EdU) incorporation, wound healing, and Tunel assay, silencing of endogenous circWDR37 attenuated proliferation and cell-cycle progression in hypoxia-exposed human PASMCs in vitro. Furthermore, bioinformatics and Luciferase assay showed that circWDR37 directly sponged hsa-miR-138-5p (miR-138) and was involved in the immunoregulatory and inflammatory processes of PAH. Together, these studies suggested new insights into circRNA regulated the pathology of PAH, providing a new potential therapeutic target for PAH treatment.
Highlights
Pulmonary arterial hypertension (PAH) is a progressive disorder defined by a mean pulmonary artery pressure ðmPAPÞ ≥ 25 mmHg
Resulting from the restricted blood flow through pulmonary artery (PA) circulation, the pathological increases in pulmonary vascular resistance (PVR) initiate the right ventricular (RV) compensatory responses
The pathogenesis of PAH is still unclear, the abnormal remodeling of pulmonary vessel walls caused by excessive pulmonary arterial smooth muscle cell (PASMC) proliferation is known to play an important role in the development of PAH [2]
Summary
Pulmonary arterial hypertension (PAH) is a progressive disorder defined by a mean pulmonary artery pressure ðmPAPÞ ≥ 25 mmHg. The pathogenesis of PAH is still unclear, the abnormal remodeling of pulmonary vessel walls caused by excessive pulmonary arterial smooth muscle cell (PASMC) proliferation is known to play an important role in the development of PAH [2]. The most downregulated circRNA, hsa_ circNFXL1_009, plays an important role in the hypoxic proliferation of pulmonary arterial smooth muscle cells (hPASMCs), while the function of the upregulated circRNAs in PAH remains unclear. The molecular and cellular mechanisms underlying hypoxic vascular remodeling are still unclear, the role of noncoding RNA mediated posttranscriptional regulation in apoptosis, proliferation, migration, and other pathological processes has been established. Given the crucial role of noncoding RNA in PAH, circWDR37 is indicated to be involved in hypoxic PAH.
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