Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, People's Republic of China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China.
Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People's Republic of China; JiNan Key Laboratory of Cardiovascular Disease, Jinan, China.
Biochim Biophys Acta Mol Cell Res. 2024 Dec;1871(8):119852. doi: 10.1016/j.bbamcr.2024.119852. Epub 2024 Sep 30.
Endoplasmic reticulum stress-induced cell apoptosis is a pivotal mechanism underlying the progression of cardiac hypertrophy. NLRX1, a member of the NOD-like receptor family, modulates various cellular processes, including STING, NF-κB, MAPK pathways, reactive oxygen species production, essential metabolic pathways, autophagy and cell death. Emerging evidence suggests that NLRX1 may offer protection against diverse cardiac diseases. However, the impacts and mechanisms of NLRX1 on endoplasmic reticulum stress in cardiac hypertrophy remains largely unexplored. In our study, we observed that the NLRX1 and phosphorylated STING (p-STING) were highly expressed in both hypertrophic mouse heart and cellular model of cardiac hypertrophy. Whereas over-expression of NLRX1 mitigated the expression levels of p-STING, as well as the endoplasmic reticulum stress markers, including transcription activating factor 4 (ATF4), C/EBP homologous protein (CHOP) and the ratios of phosphorylated PERK to PERK, phosphorylated IRE1 to IRE1 and phosphorylated eIF2α to eIF2α in an Angiotensin II (Ang II)-induced cellular model of cardiac hypertrophy. Importantly, the protective effects of NLRX1 were attenuated upon pretreatment with the STING agonist, DMXAA. Our findings provide the evidence that NLRX1 attenuates the PERK-eIF2α-ATF4-CHOP axis of endoplasmic reticulum stress response via inhibition of p-STING in Ang II-treated cardiomyocytes, thereby ameliorating the development of cardiac hypertrophy.
内质网应激诱导的细胞凋亡是心肌肥厚进展的关键机制。NLRX1 是 NOD 样受体家族的成员，调节包括 STING、NF-κB、MAPK 途径、活性氧产生、必需代谢途径、自噬和细胞死亡在内的各种细胞过程。新出现的证据表明，NLRX1 可能对多种心脏疾病提供保护。然而，NLRX1 对心肌肥厚内质网应激的影响和机制在很大程度上仍未得到探索。在我们的研究中，我们观察到 NLRX1 和磷酸化 STING（p-STING）在肥大的小鼠心脏和心肌肥厚的细胞模型中均高度表达。而 NLRX1 的过表达减轻了 p-STING 的表达水平，以及内质网应激标志物，包括转录激活因子 4（ATF4）、C/EBP 同源蛋白（CHOP）以及磷酸化 PERK 与 PERK、磷酸化 IRE1 与 IRE1 和磷酸化 eIF2α 与 eIF2α 的比值在血管紧张素 II（Ang II）诱导的心肌肥厚细胞模型中。重要的是，STING 激动剂 DMXAA 预处理减弱了 NLRX1 的保护作用。我们的研究结果提供了证据，表明 NLRX1 通过抑制 Ang II 处理的心肌细胞中的 p-STING，减轻 PERK-eIF2α-ATF4-CHOP 轴的内质网应激反应，从而改善心肌肥厚的发展。
