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Melatonin enhances atherosclerotic plaque stability by inducing prolyl-4-hydroxylase α1 expression

Li, Hongxuana; Li, Jingyuana; Jiang, Xiuxinb; Liu, Shangmingc; Liu, Yana; Chen, Weiqiand; Yang, Jianmina; Zhang, Chenga; Zhang, Wenchenga

doi: 10.1097/HJH.0000000000001979
ORIGINAL PAPERS: Organ damage/mechanistic aspects

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 α1 (P4Hα1). Mechanistically, melatonin increased Akt phosphorylation and transcriptional activation of specificity protein 1 (Sp1), which bound with the P4Hα1 promoter and then induced P4Hα1 expression. Pretreatment with either Akt inhibitor LY294002 or Sp1 inhibitor mithramycin A (MTM) could inhibit melatonin-induced P4Hα1 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 P4Hα1, which was reversed by MTM.

Conclusion: We propose that melatonin supplementation may provide a novel and promising approach to atherosclerosis treatment.

aThe Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University

bDepartment of General Surgery, Qilu Hospital of Shandong University

cKey Laboratory of the Ministry of Education for Experimental Teratology, Department of Histology and Embryology, Shandong University School of Medicine, Jinan

dDepartment of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou, China

Correspondence to Wencheng Zhang, No. 107, Wen Hua Xi Rd, Jinan, Shandong 250012, China. Tel: +86 531 82169258; fax: +86 531 82169257; e-mail:

Abbreviations: ECM, extracellularmatrix; MMPs, matrix metalloproteinases; SMCs, smooth muscle cells; VSMCs, vascular smooth muscle cells

Received 23 March, 2018

Accepted 26 September, 2018

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