COPD airway epithelial cell-derived extracellular vesicles promoted endothelial dysfunction and accelerated atherosclerosis in ApoE-/- mice via downregulation of miR-141-3p and upregulation of PDCD4.
Do COPD airway epithelial cell-derived EVs promote endothelial dysfunction and atherosclerosis?
COPD airway epithelial cell-derived EVs promote endothelial dysfunction and accelerate atherosclerosis via the miR-141-3p/PDCD4 signaling axis.
Abstract Rationale Chronic obstructive pulmonary disease (COPD) frequently coexists with extrapulmonary comorbidities, most importanly cardiovascular diseases(CVD). Atherosclerosis represents the fundamental pathological substrate of most CVDs, yet the mechanisms linking COPD to atherosclerosis remain poorly understood. Increasing evidence suggests that extracellular vesicles (EVs) serve as crucial mediators of intercellular and inter-organ communication and may play an essential role in systemic complications associated with COPD. The present study aimed to determine whether airway epithelial cells (AECs)-derived EVs from COPD patients contribute to endothelial dysfunction and atherosclerosis, and to elucidate the underlying molecular mechanisms driving these processes. Methods Primary AECs were obtained from individuals with COPD and healthy control subjects. EVs were isolated from cell culture supernatants and characterized using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting for established EV markers. Human umbilical vein endothelial cells (HUVECs) were treated with AECs-derived EVs to assess endothelial inflammatory responses, apoptosis, and monocyte adhesion. For in vivo studies, ApoE-/- mice fed a high-fat diet received repeated tail-vein injections of COPD or control AECs-derived EVs, followed by evaluation of atherosclerotic lesion formation. To explore the molecular mechanism, the role of microRNA-141-3p (miR-141-3p) was investigated using gain- and loss-of-function experiments. Results EVs derived from COPD AECs markedly enhanced the expression of inflammatory cytokines and adhesion molecules in HUVECs, promoted endothelial apoptosis, and increased monocyte adhesion. In ApoE-/- mice, administration of COPD AEC-derived EVs significantly accelerated atherosclerotic plaque development compared with control EVs. Mechanistically, miR-141-3p was markedly downregulated in COPD-derived EVs. Functional analyses revealed that miR-141-3p directly binds to the 3’ untranslated region of programmed cell death 4 (PDCD4), a well-established pro-atherogenic gene, thereby modulating its expression. Restoration of miR-141-3p levels in COPD-derived EVs suppressed PDCD4 expression, mitigated endothelial inflammation and apoptosis, and attenuated atherosclerotic progression in both cellular and animal models. Conclusion These findings demonstrate that COPD airway epithelial cell-derived EVs promote endothelial dysfunction and accelerate atherosclerosis through the delivery of reduced levels of miR-141-3p, resulting in PDCD4 upregulation and vascular injury. Supplementation of miR-141-3p effectively counteracts these pathogenic effects, suggesting that the miR-141-3p/PDCD4 signaling axis represents a novel mechanistic link between COPD and atherosclerosis. Targeting this axis may provide a promising therapeutic strategy to prevent cardiovascular complications in patients with COPD. This abstract is funded by: National Natural Science Foundation of China (Grant No. 82370047, No. 82090014)
Wang et al. (Fri,) conducted a other in COPD and atherosclerosis. COPD AECs-derived EVs vs. Control AECs-derived EVs was evaluated on Endothelial inflammatory responses, apoptosis, monocyte adhesion, and atherosclerotic lesion formation. COPD airway epithelial cell-derived extracellular vesicles promoted endothelial dysfunction and accelerated atherosclerosis in ApoE-/- mice via downregulation of miR-141-3p and upregulation of PDCD4.