Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou; Department of Cardiology, The Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang.
Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang.
Eur J Histochem. 2024 Apr 29;68(2):4019. doi: 10.4081/ejh.2024.4019.
Sepsis-induced myocardial dysfunction (SIMD) is associated with poor prognosis and increased mortality in patients with sepsis. Cytokines are important regulators of both the initiation and progression of sepsis. Interleukin-15 (IL-15), a pro-inflammatory cytokine, has been linked to protective effects against myocardial infarction and myocarditis. However, the role of IL-15 in SIMD remains unclear. We established a mouse model of SIMD via cecal ligation puncture (CLP) surgery and a cell model of myocardial injury via lipopolysaccharide (LPS) stimulation. IL-15 expression was prominently upregulated in septic hearts as well as cardiomyocytes challenged with LPS. IL-15 pretreatment attenuated cardiac inflammation and cell apoptosis and improved cardiac function in the CLP model. Similar cardioprotective effects of IL-15 pretreatment were observed in vitro. As expected, IL-15 knockdown had the opposite effect on LPS-stimulated cardiomyocytes. Mechanistically, we found that IL-15 pretreatment reduced the expression of the pro-apoptotic proteins cleaved caspase-3 and Bax and upregulated the anti-apoptotic protein Bcl-2. RNA sequencing and Western blotting further confirmed that IL-15 pretreatment suppressed the activation of nuclear factor kappa B (NF-κB) signaling in mice with sepsis. Besides, the addition of NF-κB inhibitor can significantly attenuate cardiomyocyte apoptosis compared to the control findings. Our results suggest that IL-15 pretreatment attenuated the cardiac inflammatory responses and reduced cardiomyocyte apoptosis by partially inhibiting NF-κB signaling in vivo and in vitro, thereby improving cardiac function in mice with sepsis. These findings highlight a promising therapeutic strategy for SIMD.
脓毒症诱导的心肌功能障碍（SIMD）与脓毒症患者的预后不良和死亡率增加有关。细胞因子是脓毒症发生和发展的重要调节因子。白细胞介素-15（IL-15），一种促炎细胞因子，与心肌梗死和心肌炎的保护作用有关。然而，IL-15 在 SIMD 中的作用尚不清楚。我们通过盲肠结扎穿孔（CLP）手术建立了 SIMD 小鼠模型，并通过脂多糖（LPS）刺激建立了心肌损伤细胞模型。在脓毒症心脏以及受到 LPS 刺激的心肌细胞中，IL-15 的表达明显上调。IL-15 预处理减轻了 CLP 模型中的心脏炎症和细胞凋亡，改善了心脏功能。在体外，IL-15 预处理也观察到了类似的心脏保护作用。正如预期的那样，IL-15 敲低对 LPS 刺激的心肌细胞产生了相反的效果。机制上，我们发现 IL-15 预处理降低了促凋亡蛋白 cleaved caspase-3 和 Bax 的表达，并上调了抗凋亡蛋白 Bcl-2。RNA 测序和 Western blot 进一步证实，IL-15 预处理抑制了脓毒症小鼠中核因子 kappa B（NF-κB）信号的激活。此外，与对照组相比，添加 NF-κB 抑制剂可显著减轻心肌细胞凋亡。我们的研究结果表明，IL-15 预处理通过部分抑制体内和体外的 NF-κB 信号通路，减轻了脓毒症小鼠的心脏炎症反应并减少了心肌细胞凋亡，从而改善了脓毒症小鼠的心脏功能。这些发现为 SIMD 提供了一种有前途的治疗策略。
