Deletion of METTL14, a key methylation regulator, attenuates vascular ageing.

Background And Aims: Vascular ageing often accompanies inflammation, contributing to the onset of local or systemic vascular diseases. Nevertheless, limited research focuses on pivotal factors triggering chronic vascular inflammation and associated pathological changes. This study aimed to investigate the role of methyltransferase-like protein 14 (METTL14) in inflammation in the pathogenesis of vascular ageing.

Methods: The natural ageing mouse model, D-galactose induced ageing mouse model, and endothelial cell-specific METTL14 knockout mice were generated. The roles of METTL14 in vascular ageing were investigated in human, mice, and various endothelial cells.

Results: Up-regulation of METTL14 was observed in the aortic endothelial cells of aged mice, aged humans, and senescent human umbilical vein endothelial cells, human aortic endothelial cells, and mice aortic endothelial cells. Endothelium-specific knockdown or knockout of METTL14 notably inhibited arterial stiffness, arterial remodelling, and endothelial senescence, whereas endothelium-specific overexpression of METTL14 yielded opposing effects. At the cellular level, METTL14 knockdown ameliorated cellular senescence, inflammatory responses, and oxidative stress in senescent endothelial cells. Mechanistically, METTL14 facilitated m6A modification of Toll-like receptor 4 (TLR4) mRNA, thereby enhancing its stability. Knockdown of TLR4 reversed the detrimental effects of METTL14 on vascular ageing. Importantly, vascular ageing, along with related atherosclerosis and arteriosclerosis, positively correlated with blood METTL14 and TLR4 elevations in humans.

Conclusions: This study hints at the role of METTL14/TLR4 signalling in the pathogenesis of vascular ageing, and METTL14 knockdown emerges as a potential therapeutic strategy for mitigating vascular ageing and associated vascular diseases.