Melatonin Enhances Atherosclerotic Plaque Stability By Inducing Prolyl-4-Hydroxylase Alpha 1 Expression

Objective: Melatonin, an endogenous neurohormone secreted predominately by the pineal gland, has a variety of physiological functions. However, its protective role in atherosclerosis is not clear. In this study, we sought to investigate the potential effects of melatonin in modulating atherosclerotic plaque stability in apolipoprotein E knockout (ApoE(-/-)) mice.Method and results: Smooth muscle cells were treated with melatonin, which significantly increased mRNA and protein levels of a key intracellular enzyme essential for collagen maturation and secretion, prolyl-4-hydroxylase alpha 1 (P4H alpha 1). Mechanistically, melatonin increased Akt phosphorylation and transcriptional activation of specificity protein 1 (Sp1), which bound with the P4H alpha 1 promoter and then induced P4H alpha 1 expression. Pretreatment with either Akt inhibitor LY294002 or Sp1 inhibitor mithramycin A (MTM) could inhibit melatonin-induced P4H alpha 1 expression. Finally, atherosclerotic lesions were induced by placing a perivascular collar on the right common carotid artery of ApoE(-/-) mice, which were received with or without different doses of melatonin or MTM. High-dose melatonin enhanced atherosclerotic plaque stability in ApoE(-/-) mice in vivo by inducing the expression of P4H alpha 1, which was reversed by MTM.Conclusion: We propose that melatonin supplementation may provide a novel and promising approach to atherosclerosis treatment.