miR-375-3p/STX6 Exacerbates Atherosclerosis by Promoting Endothelial Cell Senescence via Activation of TGF-Beta...

Atherosclerosis, a key pathological basis of cardio-cerebrovascular diseases, is closely associated with aging and endothelial cell senescence. The role of microRNAs (miRNAs) in regulating endothelial cell senescence and atherosclerosis remains incompletely understood. In this study, we discovered that miR-375-3p expression was significantly elevated in the serum of both aged and atherosclerotic mice. Overexpression of miR-375-3p induced endothelial cell senescence, evidenced by increased senescence-associated β-galactosidase (SA-β-gal) staining, upregulation of p15, IL6, and IL8, and inhibited cell colony formation. In vivo inhibition of miR-375-3p in ApoE^-/- mice markedly reduced atherosclerotic plaque formation. We further identified STX6 as a direct target of miR-375-3p, and its overexpression rescued the senescence-related phenotypes induced by miR-375-3p. Mechanistically, the miR-375-3p/STX6 signaling axis promoted endothelial cell senescence via the SMAD2/p15 pathway in a SMAD2-dependent manner, and overexpression of STX6 attenuated atherosclerosis progression in mice. Together, our findings highlight the miR-375-3p/STX6 axis as a critical regulator of endothelial cell senescence and a potential translational use in the prevention of atherosclerosis and related diseases.