Background:

Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism.

Methods:

Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay.

Results:

Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages.

Conclusions:

Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

中文翻译：

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核仁素通过调节巨噬细胞极化改善心肌梗塞恢复过程中的心脏功能

 背景：

核仁素在细胞存活和增殖途径中具有多种功能。我们前期的研究表明核仁素可以通过促进心肌血管生成、减少心肌细胞凋亡来显着减轻心肌缺血再灌注损伤。在本研究中，我们试图确定核仁素在心肌梗死（MI）损伤恢复中的作用及其潜在机制。

 方法：

6~8周龄雄性BALB/c小鼠结扎左冠状动脉前降支建立心肌梗死模型。通过心肌内注射表达核仁素特异性小干扰RNA的慢病毒载体，心脏中核仁素的表达下调。通过实时聚合酶链反应、流式细胞术和免疫荧光测量巨噬细胞浸润和极化。通过酶联免疫吸附测定检测细胞因子。

 结果：

MI诱导后心肌中核仁素的表达在早期显着降低，在晚期升高。核仁素敲低会损害心脏收缩和舒张功能，并降低心肌梗死后的存活率。 MI后心肌中巨噬细胞浸润增加。 MI后早期（2天）大多数巨噬细胞属于M1表型，而M2表型在MI后后期大幅增加。心肌中核仁素的敲低导致 M2 巨噬细胞极化减少，但对 MI 后巨噬细胞浸润没有影响。此外，RAW 264.7 巨噬细胞中核仁素上调 M2 巨噬细胞极化的关键调节因子 Notch3 和 STAT6。

 结论：

缺乏核仁素会减少 M2 巨噬细胞极化，从而损害 MI 后恢复过程中的心脏功能。这一发现可能为缺血性心脏病提供了一种新的治疗选择。