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心脏原位巨噬细胞在小鼠心肌梗死后心脏修复中的作用

The role of cardiac resident macrophages in heart repair following myocardial infarction in mice

    摘要
  • 摘要:
    目的 探讨心脏原位巨噬细胞在小鼠心肌梗死后心脏修复中的作用及其机制。
    方法 将巨噬细胞特异性Cre工具鼠（Cx3cr1CreER–YFP小鼠）与双重转基因小鼠（R26tdTomato/DTR小鼠）进行杂交，获得心脏原位巨噬细胞特异性红色荧光标记小鼠。选择60只Cx3cr1CreER–YFP：R26Td/DTR杂交小鼠，随机分为4组：假手术组（Sham组）、白喉毒素+假手术组（DT+Sham组）、心肌梗死模型组（MI组）和白喉毒素+心肌梗死模型组（DT+MI组），每组15只小鼠。MI组和DT+MI组采用结扎冠状动脉左前降支法进行心肌梗死造模，DT+MI组小鼠使用白喉毒素（diphtheria toxin, DT）诱导心脏组织中原位巨噬细胞的缺失，构建心脏原位巨噬细胞敲除模型。小鼠心肌梗死造模第5天，对小鼠心脏组织切片进行苏木精和伊红（H-E）染色，观察炎症浸润情况以及心肌梗死面积；造模第14天，采用超声心动图测定小鼠心功能相关指标，并检测炎性细胞因子mRNA表达水平。
    结果 与MI组相比，DT+MI组小鼠心脏原位巨噬细胞明显减少（53.75±4.62）vs（6.37±1.25）, P＜0.05。心肌梗死造模14 d，与MI组相比，DT+MI组小鼠左心室舒张末期内径（5.11±0.22）mm vs（5.92±0.26）mm, P＜0.05和收缩末期内径（4.77±0.17）mm vs（5.38±0.16）mm, P＜0.05显著增大，而射血分数显著降低（27.76±1.20）% vs（17.61±0.94）%，P＜0.05；此外，DT+MI组小鼠心脏炎性细胞因子表达水平上升，炎症细胞浸润增加，心肌梗死面积明显增大。DT+MI组小鼠NF-κB/p-P65的蛋白表达水平显著高于MI组（0.28±0.14）vs（1.09±0.12）, P＜0.05。
    结论 心脏原位巨噬细胞在心肌梗死后通过减轻炎症细胞浸润和心肌梗死面积，在心肌梗死后心脏组织修复中发挥重要作用。

     

    Abstract:
    Objective To explore the role and mechanism of cardiac resident macrophages in heart repair after myocardial infarction in mice.
    Methods Macrophage-specific Cre tool mice (CX3CR1CreER–YFP mice) with doubly transgenic mice (R26tdTomato/DTR mice) were hybridized to obtain cardiac resident macrophage-specific red fluorescent labels in mice. Sixty Cx3cr1CreER-YFP:R26Td/DTR hybrid mice were randomly divided into 4 groups: Sham group, DT+Sham group, MI group, and DT+MI group, with 15 mice in each group. MI group and DT+MI group underwent myocardial infarction modeling by ligating the left anterior descending coronary artery. The DT+MI group mice were induced to deplete resident macrophages in the heart tissue using diphtheria toxin (DT) to establish a cardiac resident macrophage knockout model. On the 5th day after myocardial infarction modeling, heart tissue slices of mice were stained with H-E to observe inflammation infiltration and myocardial infarct size were calculated; on the 14th day of modeling, echocardiography was used to measure cardiac function-related parameters in mice, and mRNA expression levels of inflammatory cytokines were detected.
    Results Compared with the MI group, the DT+MI group mice showed a significant reduction in cardiac resident macrophages (53.75±4.62 vs 6.37±1.25, P＜0.05). On the 14th day after myocardial infarction modeling, compared with the MI group, the DT+MI group mice had significantly increased left ventricular end-diastolic diameter (5.11±0.22 mm vs 5.92±0.26 mm, P＜0.05) and left ventricular end-systolic diameter (4.77±0.17 mm vs 5.38±0.16 mm, P＜0.05), while the ejection fraction significantly decreased (27.76±1.20% vs 17.61±0.94%, P＜0.05); in addition, the DT+MI group mice showed increased expression levels of inflammatory cytokines, increased inflammatory cell infiltration, and significantly larger myocardial infarct size. The protein expression levels of NF-κB/p-P65 in DT+MI group mice were significantly higher than those in the MI group (0.28±0.14 vs 1.09±0.12, P＜0.05).
    Conclusions Cardiac resident macrophages play an important role in heart tissue repair after myocardial infarction by reducing inflammation cell infiltration and myocardial infarct size.

     

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