Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα-dependent manner.

Authors:
Song Ding
Song Ding
Ren Ji Hospital
China
Nan Lin
Nan Lin
Washington University School of Medicine
United States
Xincheng Sheng
Xincheng Sheng
Ren Ji Hospital
Yichao Zhao
Yichao Zhao
Shanghai Renji Hospital
China
Yuanyuan Su
Yuanyuan Su
Soochow University
China
Longwei Xu
Longwei Xu
Ren Ji Hospital
Renyang Tong
Renyang Tong
Ren Ji Hospital
Yang Yan
Yang Yan
Shanghai Tenth People's Hospital
China

J Pineal Res 2019 Apr 22:e12581. Epub 2019 Apr 22.

State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China.

Rupture of vulnerable plaques is the main trigger of acute cardio-cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture-prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor-related orphan receptor-α (RORα) mediated melatonin-exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte-derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα-STATs pathway in a RORα-dependent manner. In summary, our data provided the first evidence that melatonin-RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture-prone vulnerable plaques.

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Source
https://onlinelibrary.wiley.com/doi/abs/10.1111/jpi.12581
Publisher Site
http://dx.doi.org/10.1111/jpi.12581DOI Listing
April 2019
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