Department of Cardiology, the First Affiliated Hospital, Anhui Medical University, Hefei, China; Post-doctoral Station of Clinical Medicine, Anhui Medical University, Hefei, China.
Operating Room, the First Affiliated Hospital, Anhui Medical University, Hefei, China.
Vascul Pharmacol. 2020 Apr;127:106659. doi: 10.1016/j.vph.2020.106659. Epub 2020 Feb 15.
Macrophage plays critical roles in the pathogenesis of atherosclerosis (AS), and is an attractive target for detecting and treating vulnerable plaque. Our previous study showed that melatonin (MLT) ameliorated AS by suppressing the pro-inflammatory Toll-like receptor 4/nuclear factor kappa B system in high-fat-fed rabbit. However, it is unknown whether the anti-atherosclerotic properties of MLT are associated with the upregulation of anti-inflammatory hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) system. In present study, we examined whether MLT could inhibit macrophage infiltration and promote plaque stabilization by upregulating HGF/c-Met system with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) assessment in AS rabbit. Rabbits in this study were randomly divided into three groups and treated with a standard diet, high-fat diet, and high-fat diet plus 10 mg/kg/day MLT for 12 weeks, respectively. MLT treatment significantly reversed spotty signal void in 3D-TOF MRI, standard signal intensity reduction in T2WI MRI and aortic luminal area reduction in 2D-TOF MRI of the atherosclerotic abdominal aorta 72 h after USPIO injection. It also decreased serum interleukin-6 (IL-6), intima/media thickness ratio of the abdominal aorta, CD68 and iron-positive areas in the aortic intima, and increased serum IL-10, HGF and c-Met protein expression and the accumulation of vascular smooth muscle cell and collagen fiber in the aortic intima of AS rabbit. Our data demonstrated that MLT significantly decreased plaque macrophage infiltration and promoted plaque stability in AS rabbit assessed by USPIO-enhanced MRI. Remarkably, it was very first revealed that upregulation of anti-inflammatory HGF/c-Met system might contribute to the atheroprotective mechanisms of MLT.
巨噬细胞在动脉粥样硬化（AS）的发病机制中起着关键作用，是检测和治疗易损斑块的有吸引力的靶点。我们之前的研究表明，褪黑素（MLT）通过抑制高脂肪喂养兔的促炎 Toll 样受体 4/核因子 kappa B 系统来改善 AS。然而，尚不清楚 MLT 的抗动脉粥样硬化特性是否与抗炎肝细胞生长因子（HGF）/间质上皮转化因子（c-Met）系统的上调有关。在本研究中，我们通过超顺磁性氧化铁（USPIO）增强磁共振成像（MRI）评估，研究了 MLT 是否可以通过上调 HGF/c-Met 系统抑制巨噬细胞浸润并促进斑块稳定。本研究中的兔子随机分为三组，分别给予标准饮食、高脂肪饮食和高脂肪饮食加 10mg/kg/天 MLT 治疗 12 周。MLT 治疗可显著逆转 3D-TOF MRI 中的点状信号缺失、T2WI MRI 中的标准信号强度降低和 2D-TOF MRI 中的腹主动脉腔面积减少，在 USPIO 注射后 72 小时。它还降低了血清白细胞介素 6（IL-6）、腹主动脉内膜/中膜厚度比、CD68 和主动脉内膜中铁阳性面积，增加了血清白细胞介素 10（IL-10）、HGF 和 c-Met 蛋白表达以及主动脉内膜中血管平滑肌细胞和胶原纤维的积累在 AS 兔中。我们的数据表明，MLT 可通过 USPIO 增强 MRI 显著减少 AS 兔斑块中的巨噬细胞浸润并促进斑块稳定。值得注意的是，首次揭示了抗炎 HGF/c-Met 系统的上调可能有助于 MLT 的抗动脉粥样硬化机制。
