Department of Biomedical Science, Jungwon University, Goesan-gun 28024, Korea.
Bio-Evaluation Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju 28116, Korea.
Int J Mol Sci. 2022 Jan 27;23(3):1489. doi: 10.3390/ijms23031489.
Protein kinase B2 (AKT2) is involved in various cardiomyocyte signaling processes, including those important for survival and metabolism. Coxsackievirus B3 (CVB3) is one of the most common pathogens that cause myocarditis in humans. The role of AKT2 in CVB3 infection is not yet well understood. We used a cardiac-specific AKT2 knockout (KO) mouse to determine the role of AKT2 in CVB3-mediated myocarditis. CVB3 was injected intraperitoneally into wild-type (WT) and KO mice. The mice's survival rate was recorded: survival in KO mice was significantly decreased compared with WT mice (WT vs. KO: 73.3 vs. 27.1%). Myocardial damage and inflammation were significantly increased in the hearts of KO mice compared with those of WT mice. Moreover, from surface ECG, AKT2 KO mice showed a prolonged atria and ventricle conduction time (PR interval, WT vs. KO: 47.27 ± 1.17 vs. 64.79 ± 7.17 ms). AKT2 deletion induced severe myocarditis and cardiac dysfunction due to CVB3 infection. According to real-time PCR, the mRNA level of IL-1, IL-6, and TNF-α decreased significantly in KO mice compared with WT mice on Days 5 after infection. In addition, innate immune response antiviral effectors, Type I interferon (interferon-α and β), and p62, were dramatically suppressed in the heart of KO mice. In particular, the adult cardiac myocytes isolated from the heart showed high induction of TLR4 protein in KO mice in comparison with WT. AKT2 deletion suppressed the activation of Type I interferon and p62 transcription in CVB3 infection. In cardiac myocytes, AKT2 is a key signaling molecule for the heart from damage through the activation of innate immunity during acute myocarditis.
蛋白激酶 B2 (AKT2) 参与各种心肌细胞信号转导过程，包括对生存和代谢很重要的过程。柯萨奇病毒 B3 (CVB3) 是人类心肌炎最常见的病原体之一。AKT2 在 CVB3 感染中的作用尚未得到很好的理解。我们使用心脏特异性 AKT2 敲除 (KO) 小鼠来确定 AKT2 在 CVB3 介导的心肌炎中的作用。将 CVB3 腹腔内注射到野生型 (WT) 和 KO 小鼠中。记录小鼠的存活率：与 WT 小鼠相比，KO 小鼠的存活率明显降低（WT 与 KO：73.3%与 27.1%）。与 WT 小鼠相比，KO 小鼠的心肌损伤和炎症明显增加。此外，从体表心电图来看，AKT2 KO 小鼠的心房和心室传导时间延长（PR 间期，WT 与 KO：47.27±1.17 毫秒与 64.79±7.17 毫秒）。由于 CVB3 感染，AKT2 缺失导致严重的心肌炎和心脏功能障碍。实时 PCR 结果显示，与 WT 小鼠相比，感染后 5 天 KO 小鼠的 IL-1、IL-6 和 TNF-αmRNA 水平显著降低。此外，在 KO 小鼠的心脏中，I 型干扰素（干扰素-α和β）和 p62 等先天免疫反应抗病毒效应物显著受到抑制。特别是，与 WT 小鼠相比，从 KO 小鼠心脏分离的成年心肌细胞中 TLR4 蛋白的诱导明显增加。AKT2 缺失抑制了 CVB3 感染中 I 型干扰素和 p62 转录的激活。在心肌细胞中，AKT2 是急性心肌炎中从损伤到激活先天免疫的心脏关键信号分子。
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