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

J Pineal Res. 2019 Sep;67(2):e12581. doi: 10.1111/jpi.12581. Epub 2019 May 14.Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORα-dependent manner.Ding S1, Lin N1, Sheng X1, Zhao Y1, Su Y1, Xu L1, Tong R1, Yan Y1, Fu Y1, He J1, Gao Y1, Yuan A1, Ye L2, Reiter RJ3, Pu J1.Author information1State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China.2National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore City, Singapore.3Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, Texas.AbstractRupture 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.© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.KEYWORDS: RAR-related orphan receptor; atherosclerosis; macrophage polarization; melatonin; nuclear receptor; vulnerable plaquesPMID: 31009101 DOI: 10.1111/jpi.12581 [Indexed for MEDLINE] ShareMeSH terms, Substances, Grant supportMeSH termsAnimalsAtherosclerosis/drug therapyAtherosclerosis/geneticsAtherosclerosis/metabolism*Atherosclerosis/pathologyHumansMacrophages/metabolism*Macrophages/pathologyMaleMelatonin/pharmacology*MiceMice, Knockout, ApoENuclear Receptor Subfamily 1, Group F, Member 1/geneticsNuclear Receptor Subfamily 1, Group F, Member 1/metabolism*Plaque, Atherosclerotic/drug therapyPlaque, Atherosclerotic/geneticsPlaque, Atherosclerotic/metabolism*Plaque, Atherosclerotic/pathologySignal Transduction/drug effects*Signal Transduction/geneticsSubstancesNuclear Receptor Subfamily 1, Group F, Member 1Rora protein, mouseMelatoninGrant support81625002/National Science Fund for Distinguished Young Scholars/81400261/National Natural Science Foundation of China/81470389/National Natural Science Foundation of China/81500221/National Natural Science Foundation of China/81800307/National Natural Science Foundation of China/91839301/National Natural Science Foundation of China/18XD1402400/Shanghai Outstanding Academic Leaders Program/YG2016MS45/Shanghai Jiao Tong University/18YF1413000/Shanghai Sailing Program/18YF1413500/Shanghai Sailing Program/LinkOut - more resourcesFull Text SourcesWileyMedicalAtherosclerosis - MedlinePlus Health InformationMiscellaneousMELATONIN - Hazardous Substances Data BankNCI CPTAC Assay Portal

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