Macrophage-derived MMP-9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits
Macrophage-derived MMP-9 enhances the progression of atherosclerotic lesions and vascular calcification in transgenic rabbits
复制标题
巨噬细胞衍生的 MMP-9 促进转基因兔动脉粥样硬化病变和血管钙化的进展
DOI：
10.1111/jcmm.15087
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发表时间：
2020-03-03
影响因子：
5.3
通讯作者：
Fan, Jianglin
中科院分区：
文献类型：
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作者：
Chen, Yajie;Waqar, Ahmed Bilal;Fan, Jianglin
基质金属蛋白酶-9（MMP-9），或明胶酶B，已被假设参与动脉粥样硬化的进展。在动脉壁中，积聚的巨噬细胞分泌大量的MMP-9，但其在动脉粥样硬化中的病理生理功能尚未完全阐明。为了检验巨噬细胞来源的MMP-9可能影响动脉粥样硬化的假设，我们建立了MMP-9转基因（Tg）兔，在清道夫受体A增强子/启动子的控制下过表达兔MMP-9基因，并检查了它们对胆固醇饮食诱导的动脉粥样硬化的易感性。给转基因兔沿着非转基因兔喂食胆固醇饲料16周和28周，比较它们的主动脉和冠状动脉粥样硬化。在28周时，雌性Tg兔的主动脉病变总面积显著增加;然而，病理学检查显示，与非Tg兔相比，喂食胆固醇饲料16周或28周的Tg兔的所有病变均表现为单核细胞/巨噬细胞蓄积增加和显著的脂质核心形成。从Tg兔中分离的巨噬细胞在体外对趋化因子MCP-1表现出更高的浸润活性，并增强了在肉芽肿组织中水解细胞外基质的能力。令人惊讶的是，Tg兔的病变显示出更严重的病变，在动脉瘤和冠状动脉中都有显著的钙化。总之，巨噬细胞衍生的MMP-9促进单核细胞/巨噬细胞浸润到病变中，从而促进动脉粥样硬化的进展。病变巨噬细胞积聚增加可能促进血管钙化。
Matrix metalloproteinase-9 (MMP-9), or gelatinase B, has been hypothesized to be involved in the progression of atherosclerosis. In the arterial wall, accumulated macrophages secrete considerable amounts of MMP-9 but its pathophysiological functions in atherosclerosis have not been fully elucidated. To examine the hypothesis that macrophage-derived MMP-9 may affect atherosclerosis, we created MMP-9 transgenic (Tg) rabbits to overexpress the rabbit MMP-9 gene under the control of the scavenger receptor A enhancer/promoter and examined their susceptibility to cholesterol diet-induced atherosclerosis. Tg rabbits along with non-Tg rabbits were fed a cholesterol diet for 16 and 28 weeks, and their aortic and coronary atherosclerosis was compared. Gross aortic lesion areas were significantly increased in female Tg rabbits at 28 weeks; however, pathological examination revealed that all the lesions of Tg rabbits fed a cholesterol diet for either 16 or 28 weeks were characterized by increased monocyte/macrophage accumulation and prominent lipid core formation compared with those of non-Tg rabbits. Macrophages isolated from Tg rabbits exhibited higher infiltrative activity towards a chemoattractant, MCP-1 in vitro and augmented capability of hydrolysing extracellular matrix in granulomatous tissue. Surprisingly, the lesions of Tg rabbits showed more advanced lesions with remarkable calcification in both aortas and coronary arteries. In conclusion, macrophage-derived MMP-9 facilitates the infiltration of monocyte/macrophages into the lesions thereby enhancing the progression of atherosclerosis. Increased accumulation of lesional macrophages may promote vascular calcification.