Melatonin attenuates atherosclerotic plaque vulnerability through SIRT6-dependent regulation of vascular smooth muscle cells senescence

Rupture of vulnerable atherosclerotic plaques is a major cause of acute cardiovascular events. Vascular smooth muscle cell (VSMC) senescence promotes plaque vulnerability by impairing fibrous cap integrity. Although melatonin exhibits atheroprotective potential, its capacity to stabilize plaques by targeting VSMC senescence along with the underlying mechanisms, remains unclear. In this study, a vulnerable plaque model was established in apoE^-/- mice by partial ligation of the left carotid artery combined with a high-fat diet. Melatonin treatment substantially enhanced plaque stability, as indicated by decreased plaque burden, increased fibrous cap thickness, and an elevated collagen-to-lipid ratio. These effects were prevented by the MT membrane receptor antagonist luzindole. Melatonin markedly suppressed VSMC senescence in both plaques and hydrogen peroxide-stimulated VSMCs; this suppression was similarly abolished by luzindole. Transcriptomic analysis identified SIRT6 as the most significantly upregulated Sirtuin in response to melatonin treatment. Melatonin upregulated SIRT6 expression in a MT membrane receptor-dependent manner. Notably, VSMC-specific SIRT6 knockdown eliminated the beneficial effects of melatonin on plaque stabilization and VSMC senescence attenuation. Mechanistically, melatonin alleviated oxidative stress by activating the Nrf2 antioxidant pathway-an effect nullified by SIRT6 knockdown or inhibition. This study uncovers a novel mechanism by which melatonin mitigates atherosclerotic plaque vulnerability through inhibition of VSMC senescence. This protective action is mediated via MT membrane receptor-dependent activation of the SIRT6/Nrf2 signaling axis, culminating in reduced oxidative stress.

Melatonin; Melatonin membrane receptor; SIRT6; Vascular smooth muscle cell senescence; Vulnerable plaque.