背景:先前的研究表明,中性粒细胞胞外陷阱(NETs)在肺动脉高压(PAH)的发病机制中起关键作用。然而,尚未确定NETs对肺动脉平滑肌细胞(PASMC)影响的具体机制。这项研究的目的是阐明NETs促进PAH进展的潜在机制。
方法:本研究采用生物信息学分析来筛选与PAH发生和发展相关的潜在分子和机制。这些发现随后在人体样本中得到了验证,含有25个(CCDC25)敲低PASMC的卷曲螺旋结构域,以及野百合碱诱导的PAH大鼠模型。
结果:NET促进了PASMC的增殖,从而促进PAH的发病机制。这种现象是由跨膜受体CCDC25在PASMC上的激活介导的,随后激活ILK/β-parvin/RAC1通路。因此,PASMC中发生细胞骨架重塑和表型转化。此外,NETs水平可作为PAH严重程度的指标,也可作为缓解PAH的潜在治疗目标.
结论:这项研究阐明了NETs通过影响PASMC的功能而参与PAH的发病机制。从而突出了它们作为PAH评估和治疗的有希望的目标的潜力。
BACKGROUND: Previous studies have indicated that neutrophil extracellular traps (NETs) play a pivotal role in pathogenesis of pulmonary arterial hypertension (PAH). However, the specific mechanism underlying the impact of NETs on pulmonary artery smooth muscle cells (PASMCs) has not been determined. The objective of this study was to elucidate underlying mechanisms through which NETs contribute to progression of PAH.
METHODS: Bioinformatics analysis was employed in this study to screen for potential molecules and mechanisms associated with occurrence and development of PAH. These findings were subsequently validated in human samples, coiled-coil domain containing 25 (CCDC25) knockdown PASMCs, as well as monocrotaline-induced PAH rat model.
RESULTS: NETs promoted proliferation of PASMCs, thereby facilitating pathogenesis of PAH. This phenomenon was mediated by the activation of transmembrane receptor CCDC25 on PASMCs, which subsequently activated ILK/β-parvin/RAC1 pathway. Consequently, cytoskeletal remodeling and phenotypic transformation occur in PASMCs. Furthermore, the level of NETs could serve as an indicator of PAH severity and as potential therapeutic target for alleviating PAH.
CONCLUSIONS: This study elucidated the involvement of NETs in pathogenesis of PAH through their influence on the function of PASMCs, thereby highlighting their potential as promising targets for the evaluation and treatment of PAH.