Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Cardiovascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
BMC Cardiovasc Disord. 2022 Feb 23;22(1):69. doi: 10.1186/s12872-022-02458-3.
Myocarditis is a cardiomyopathy associated with the inflammatory response. Rosuvastatin (RS) demonstrates cardioprotective effect in the clinical setting, although its cellular and molecular mechanisms in ameliorating myocarditis are largely unknown. MG53 (muscle-specific E3 ligase Mitsugumin 53), a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. We aimed to explore whether RS mediated the repair of cardiomyocytes in an MG53-dependent manner.
The RS-induced upregulation of MG53 was determined using RT-qPCR and western blotting. A lipopolysaccharide (LPS)-induced cell inflammatory model was constructed using rat cardiac muscle cell H9C2. Inflammatory injury was evaluated according to the alterations of cell viability, mitochondrial membrane potential, cell apoptosis, and expression of pro-inflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1). Small interfering RNAs (siRNAs) were used to silence MG53. The cardioprotective effect of RS and the inhibition of this protection by MG53 silence were evaluated in the forementioned in vitro model. The underlying mechanism was finally investigated using western blotting to detected the expressions of apoptotic markers (Bcl-2, Bax, Cleaved caspase-9, Cleaved caspase-3), cell cycle regulatory factors (Cyclin A, Cyclin E1, Cyclin D1, CDK2), and components involved in NF-κB signaling pathway (p-IκBa, Iκba, p-p65, p65).
RS ameliorated LPS-induced inflammatory injury. RS upregulated the expression of MG53. MG53 was crucial for the RS-mediated repair response in vitro. Ablation of MG53 inhibited the RS-mediated protective effect. Furthermore, RS and MG53 interact in multiple signaling pathways to modulate recovery.
RS exerts cardioprotective effect in an MG53-dependent manner. MG53 may serve as a novel drug target for myocarditis treatment.
心肌炎是一种与炎症反应相关的心肌病。尽管在临床环境中，瑞舒伐他汀（RS）具有心脏保护作用，但它改善心肌炎的细胞和分子机制在很大程度上尚不清楚。MG53（肌肉特异性 E3 连接酶 Mitsugumin 53）是一种新发现的横纹肌特异性蛋白，参与骨骼肌膜修复。我们旨在探索 RS 是否通过 MG53 依赖的方式介导心肌细胞的修复。
使用 RT-qPCR 和 Western blot 确定 RS 诱导的 MG53 上调。使用大鼠心肌细胞 H9C2 构建脂多糖（LPS）诱导的细胞炎症模型。根据细胞活力、线粒体膜电位、细胞凋亡和促炎细胞因子（白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α和单核细胞趋化蛋白-1）的变化评估炎症损伤。使用小干扰 RNA（siRNA）沉默 MG53。在上述体外模型中评估 RS 的心脏保护作用和 MG53 沉默对这种保护的抑制作用。最后，使用 Western blot 检测凋亡标志物（Bcl-2、Bax、Cleaved caspase-9、Cleaved caspase-3）、细胞周期调节因子（Cyclin A、Cyclin E1、Cyclin D1、CDK2）和 NF-κB 信号通路的表达来研究潜在的机制参与的成分（p-IκBa、Iκba、p-p65、p65）。
RS 改善了 LPS 诱导的炎症损伤。RS 上调了 MG53 的表达。MG53 是 RS 介导的体外修复反应的关键。MG53 的缺失抑制了 RS 介导的保护作用。此外，RS 和 MG53 在多种信号通路中相互作用，调节恢复。
RS 以 MG53 依赖的方式发挥心脏保护作用。MG53 可能成为治疗心肌炎的新药物靶点。
