Ongoing inflammation in the heart is positively correlated with adverse remodeling, characterized by elevated levels of cytokines that stimulate activation of cardiac fibroblasts. It was found that CaMKIIδ response to Ang II or TAC triggers the accumulation of ROS in cardiomyocytes, which subsequently stimulates NF-κB/NLRP3 and leads to an increase in IL-6, IL-1β, and IL-18. This is an important causative factor in the occurrence of adverse remodeling in heart failure. Sweroside is a biologically active natural iridoids extracted from Flos. It shows potent anti-inflammatory and antioxidant activity in various cardiovascular diseases. In this study, we found that sweroside inhibited ROS-mediated NF-κB/NLRP3 in Ang II-treated cardiomyocytes by directly binding to CaMKIIδ. Knockdown of CaMKⅡδ abrogated the effect of sweroside regulation on NF-κB/NLRP3 in cardiomyocytes. AAV-CaMKⅡδ induced high expression of CaMKⅡδ in the myocardium of TAC/Ang II-mice, and the inhibitory effect of sweroside on TAC/Ang Ⅱ-induced elevation of NF-κB/NLRP3 was impeded. Sweroside showed significant inhibitory effects on CaMKIIδ/NF-κB/NLRP3 in cardiomyocytes from TAC/Ang Ⅱ-induced mice. This would be able to mitigate the adverse events of myocardial remodeling and contractile dysfunction at 8 weeks after the onset of the inflammatory response. Taken together, our findings have revealed the direct protein targets and molecular mechanisms by which sweroside improves heart failure, thereby supporting the further development of sweroside as a therapeutic agent for heart failure.

中文翻译：

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Sweroside 通过靶向 CaMKⅡδ 抑制心肌细胞中 ROS 介导的 NF-κB/NLRP3 缓解压力超负荷引起的心力衰竭


心脏中持续的炎症与不良重塑呈正相关，其特征是刺激心脏成纤维细胞活化的细胞因子水平升高。研究发现，CaMKIIδ 对 Ang II 或 TAC 的反应会触发心肌细胞中 ROS 的积累，随后刺激 NF-κB/NLRP3 并导致 IL-6、IL-1β 和 IL-18 增加。这是心力衰竭不良重构发生的重要致病因素。 Sweroside 是从花中提取的具有生物活性的天然环烯醚萜类化合物。它在各种心血管疾病中显示出有效的抗炎和抗氧化活性。在这项研究中，我们发现苦菜苷通过直接与 CaMKIIδ 结合来抑制 Ang II 处理的心肌细胞中 ROS 介导的 NF-κB/NLRP3。 CaMKⅡδ的敲低消除了苦菜苷对心肌细胞中NF-κB/NLRP3的调节作用。 AAV-CaMKⅡδ诱导TAC/Ang II小鼠心肌CaMKⅡδ高表达，而苦菜苷对TAC/Ang Ⅱ诱导的NF-κB/NLRP3升高的抑制作用被阻碍。 Sweroside 对 TAC/Ang Ⅱ 诱导的小鼠心肌细胞 CaMKIIδ/NF-κB/NLRP3 有显着的抑制作用。这将能够减轻炎症反应发生后 8 周时心肌重塑和收缩功能障碍的不良事件。总而言之，我们的研究结果揭示了苦菜苷改善心力衰竭的直接蛋白质靶点和分子机制，从而支持苦菜苷作为心力衰竭治疗剂的进一步开发。