State Key Laboratory for Oncogenes and Related Genes, Division of Cardiology, Renji Hospital, School of Medicine, Shanghai Cancer Institute, Shanghai Jiaotong University, Shanghai, China.
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore City, Singapore.
J Pineal Res. 2019 Sep;67(2):e12581. doi: 10.1111/jpi.12581. Epub 2019 May 14.
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.
易损斑块的破裂是急性心脑血管事件的主要触发因素，但将稳定的动脉粥样硬化斑块转化为易损斑块的机制在很大程度上仍不清楚。褪黑素是松果体分泌的一种吲哚胺激素，在心血管系统中发挥多种作用；然而，褪黑素对易损斑块破裂的影响及其潜在机制尚不清楚。在这里，我们通过内源性肾血管性高血压结合高胆固醇血症 ApoE 小鼠的低切应力，生成了一种易破裂的易损颈动脉斑块模型。褪黑素（口服 10mg/kg/d，持续 9 周）显著预防了易损斑块破裂，斑块内出血发生率降低（42.9%比 9.5%，P=0.014），自发斑块破裂伴管腔内血栓形成的发生率降低（38.1%比 9.5%，P=0.029）。机制研究表明，褪黑素通过抑制斑块内巨噬细胞向促炎 M1 表型分化，改善斑块内炎症，而昼夜核受体视黄酸受体相关孤儿受体-α（RORα）介导的褪黑素对易损斑块不稳定性和斑块内巨噬细胞极化的血管保护作用。对人单核细胞衍生的巨噬细胞的进一步分析证实了褪黑素通过 RORα依赖性方式调节 AMPKα-STATs 通路来调节巨噬细胞极化的作用。总之，我们的数据提供了第一个证据，表明褪黑素-RORα 轴作为一种新的内源性保护信号通路在血管中起作用，调节斑块内炎症，并稳定易破裂的易损斑块。
