College of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China.
State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing 211198, PR China.
Life Sci. 2024 Mar 15;341:122474. doi: 10.1016/j.lfs.2024.122474. Epub 2024 Feb 1.
This work sought to investigate the mechanism underlying the STING signaling pathway during myocardial infarction (MI), and explore the involvement and the role of SIRT6 in the process.
Mice underwent the surgery of permanent left anterior descending (LAD) artery constriction. Primary cardiomyocytes (CMs) and fibroblasts were subjected to hypoxia to mimic MI in vitro. STING expression was assessed in the infarct heart, and the effect of STING inhibition on cardiac fibrosis was explored. This study also evaluated the regulatory effect of STING by SIRT6 in macrophages.
STING protein was increased in the infarct heart tissue, highlighting its involvement in the post-MI inflammatory response. Hypoxia-induced death of CMs and fibroblasts contributed to the upregulation of STING in macrophages, establishing the involvement of STING in the intercellular signaling during MI. Inhibition of STING resulted in a significant reduction of cardiac fibrosis at day 14 after MI. Additionally, this study identified SIRT6 as a key regulator of STING via influencing its acetylation and ubiquitination in macrophages, providing novel insights into the posttranscriptional modification and expression of STING at the acute phase after myocardial infarction.
This work shows the key role of SIRT6/STING signaling in the pathogenesis of cardiac injury after MI, suggesting that targeting this regulatory pathway could be a promising strategy to attenuate cardiac fibrosis after MI.
本研究旨在探讨 STING 信号通路在心肌梗死（MI）中的作用机制，并探索 SIRT6 在该过程中的参与和作用。
通过永久结扎左前降支（LAD）动脉的手术使小鼠发生 MI，体外通过低氧处理原代心肌细胞（CMs）和成纤维细胞模拟 MI。评估梗死心脏中 STING 的表达，并探索 STING 抑制对心肌纤维化的影响。本研究还评估了 SIRT6 对巨噬细胞中 STING 的调节作用。
STING 蛋白在梗死心脏组织中增加，提示其参与 MI 后的炎症反应。CMs 和成纤维细胞的缺氧诱导死亡导致巨噬细胞中 STING 的上调，确立了 STING 在 MI 期间细胞间信号传递中的作用。MI 后 14 天，STING 抑制导致心肌纤维化显著减少。此外，本研究通过影响巨噬细胞中 STING 的乙酰化和泛素化，确定 SIRT6 是 STING 的关键调节因子，为心肌梗死后急性期 STING 的转录后修饰和表达提供了新的见解。
本研究表明 SIRT6/STING 信号在 MI 后心脏损伤发病机制中的关键作用，提示靶向该调节途径可能是减轻 MI 后心肌纤维化的有前途的策略。
