Key result
Inhibition of miR-Y enhances endothelial angiogenesis but increases senescent inflammatory cytokines.
Why the study?
Ageing drives vascular alterations and cardiovascular disease through endothelial senescence, and microRNAs are critical regulators of both processes whose functional roles in endothelial senescence require investigation.
Does LNA-based inhibition of miR-Y improve angiogenic capacity and modulate inflammatory signaling in non-senescent and replicative senescent human coronary artery endothelial cells?
Does LNA-based inhibition of miR-Y improve angiogenic capacity and modulate inflammatory signaling in non-senescent and replicative senescent human coronary artery endothelial cells?
Inhibition of the age-associated microRNA-Y improves angiogenic capacity in human coronary artery endothelial cells, suggesting a potential target for vascular regeneration, though it also triggers pro-inflammatory signaling in senescent cells and cell death in non-senescent cells.
Ageing is a major driver of vascular alterations, with senescent endothelial and smooth muscle cells contributing to endothelial dysfunction and the development of cardiovascular disease (CVD). MicroRNAs are critical regulators of both CVD and cellular senescence. The expression of microRNA-Y was assessed in non-senescent and replicative senescent human coronary artery endothelial cells (HCAEC) using qRT-PCR. To investigate its functional role in cellular processes and senescence, miR-Y was inhibited using a locked nucleic acid (LNA)-based inhibitor. In silico–predicted targets were validated at both mRNA and protein levels. A machine learning–based analysis of more than 1,200 miRNA datasets comprising 1,800 distinct miRNAs from tissue samples of individuals aged 20 to 90 years identified miR-Y as a key age-associated miRNA. It was significantly upregulated in aged individuals, exhibited high network centrality, and was predicted to regulate over 80% of age-related target genes. In vitro, miR-Y expression was significantly increased in replicative senescent compared to non-senescent HCAEC (p<0.05), as well as in aortic endothelial cells from old versus young mice. Transfection with an LNA inhibitor effectively reduced miR-Y levels. Functional assays demonstrated that miR-Y inhibition enhanced angiogenic capacity in both non-senescent and replicative senescent HCAEC, as evidenced by tube formation and sprouting assays (p<0.05). However, inhibition also increased cell death in non-senescent cells (p<0.05) and was associated with enlarged nuclear size. In senescent HCAEC, miR-Y inhibition led to elevated expression of the pro-inflammatory cytokines TNF-α (p<0.01), IL-1β (p<0.05), and IL-6 (p<0.05). In summary, inhibition of miR-Y improved angiogenic capacities in non-senescent and replicative senescent HCAEC, indicating a positive effect on vascular regeneration. However, its role in cellular senescence remains inconclusive and needs further evaluation. In conclusion, inhibition of miR-Y improves angiogenic capacity in both non-senescent and replicative senescent endothelial cells, suggesting a potential role in promoting vascular regeneration. However, its impact on cellular senescence and inflammatory signaling appears complex and warrants further investigation.
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Kalies et al. (2026) studied Endothelial senescence and vascular ageing. Locked nucleic acid (LNA)-based microRNA-Y (miR-Y) inhibitor vs. Uninhibited / control non-senescent and replicative senescent HCAEC was evaluated on Angiogenic capacity (tube formation and sprouting assays) and inflammatory cytokine expression in HCAEC (p=<0.05). Inhibition of age-associated miR-Y enhanced angiogenic capacity in endothelial cells (p<0.05) but increased senescent inflammatory cytokines TNF-α (p<0.01), IL-1β, and IL-6 (p<0.05).
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