Hsa_circ_0002062 Promotes the Proliferation of Pulmonary Artery Smooth Muscle Cells by Regulating the Hsa-miR-942-5p/CDK6 Signaling Pathway

Abstract

Currently, new strategies for the diagnosis and treatment of hypoxia-induced pulmonary hypertension (HPH) are urgently required. The unique features of circRNAs have unveiled a novel perspective for understanding the biological mechanisms underlying HPH and the possibility for innovative strategies for treatment of HPH. CircRNAs function as competing endogenous RNAs (CeRNA) to sequester miRNAs and regulate the expression of target genes. This study aimed to explore the roles of hsa_circ_0002062 on the biological behaviors of pulmonary artery smooth muscle cells (PASMCs) in hypoxic conditions. A number of in vitro assays, such as RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and dual-luciferase assays were performed to evaluate the interrelationship between hsa_circ_0002062, hsa-miR-942-5P, and CDK6. The potential physiological functions of hsa_circ_0002062, hsa-miR-942-5P, and CDK6 in hypoxic PASMCs were investigated through expression modulation. Our experiments demonstrated that hsa_circ_0002062 functions as a ceRNA, acts as a sponge for hsa-miR-942-5P, and consequently activates CDK6, which further promotes pulmonary vascular remodeling. Therefore, we speculate that hsa_circ_0002062 could serve as a candidate diagnostic biomarker and potential therapeutic target for HPH.

CircGSAP regulates the cell cycle of pulmonary microvascular endothelial cells via the miR-942-5p sponge in pulmonary hypertension

“…Many studies have shown that miR-942-5p regulates cell proliferation and disease progression in different types of tumors ( Li et al, 2020 ; Wang et al, 2020 ; Gu et al, 2021 ; Zhang et al, 2021 ); these findings are consistent with our results, because PMECs dysfunction in PH is a cancer cell-like phenotype. However, Wang et al found that miR-942-5p could inhibit PASMCs proliferation in vitro ( Wang et al, 2021 ), which is inconsistent with our results; a possible reason for this is the difference in the cell types studied and the cell culture conditions. Evaluating the impact of miR-942-5p on PASMCs during PH development may also help clarify the basis for this difference.…”

circNFXL1 modulates the Kv2.1 channel function in hypoxic human pulmonary artery smooth muscle cells via sponging miR-29b-2-5p as a competitive endogenous RNA

“…14 In addition, accumulating evidence suggested that the aberrant expressions of circRNAs, such as hsa_circ_0002062, hsa_circ_0022342, and hsa_circ_0016070, contribute to PASMC proliferation for PAH development. [14][15][16] Functionally, circ-calm4 acts as a molecular sponge for miRNAs, modulating cell cycle progression and pyroptosis of PASMCs via miR-337-3p/Myo10 axis and miR-124-3p/PDCD6 axis, respectively. 24,25 Furthermore, circRNAs have also been reported to regulate human pulmonary artery endothelial cells (PAEC) function in PAH development.…”

The Landscape of Noncoding RNA in Pulmonary Hypertension

“…Silencing of has_circ_0002062 prevented cell proliferation and migration in PASMCs by acting as a ceRNA targeting miR-942-5p/CDK6 axis. In addition, CDK6 inhibition by AAV in vivo prevented pulmonary vascular remodeling in a hypoxia-induced PH model [ 129 ], which suggests that the downstream target of has_circ_0002062 shows therapeutic potential. Thus, manipulation of has_circ_0002062 may be a promising therapeutic strategy for PH.…”