Ren Lingxuan, Liu Yizhen, Chen Danli, Rong Xiaoyu, Wen Jiazheng, Zheng Zihan, Chen Lifang, He Jianyu, Wang Weirong, Lin Rong
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, Shaanxi, PR China; Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
Department of Pharmacy, Xi'an Ninth Hospital Affiliated to Medical College of Xi'an Jiaotong University, Xi'an 710054, Shaanxi Province, China.
Biochim Biophys Acta Mol Cell Res. 2025 Oct;1872(7):120026. doi: 10.1016/j.bbamcr.2025.120026. Epub 2025 Jul 19.
Histone deacetylase 11 (HDAC11) is the only member of the class IV HDAC family and is involved in cardiovascular diseases (CVDs). Stress granule (SG) is non-membranous cytoplasmic foci induced by various stress conditions, and also has emerged as a key player for CVDs. However, the regulatory role of HDAC11 in SG formation and underlying mechanism during atherosclerosis remain elusive. Therefore, we aimed to investigate the effect of HDAC11 on SG in ApoE mice fed with a HFD and HUVECs induced by HO. Firstly, we found that the expression levels of SG core proteins G3BP1/2 and HDAC11 were increased in the aorta of ApoE mice fed with a HFD for 12w via analyses of Western blotting, Real-time PCR and immunofluorescence staining. In addition, endothelial-to-mesenchymal transition (EndMT) was occurred in the aorta of ApoE mice. Then, in vitro experiments demonstrated that treatment of HUVECs with HO resulted in SG formation, HDAC11 upregulation, and EndMT occurrence. Furthermore, knockdown of HDAC11 by siRNA significantly attenuated SG formation and EndMT activation in HUVECs induced by HO. Silencing of HDAC11 suppressed HO-induced EndMT activation in HUVECs, which may be attributed to increased acetylation of G3BP1/2 and the consequent impairment of SG formation. Further studies found that suppression of SG formation not only facilitated the expression of endothelial markers, but also decreased the levels of mesenchymal cell markers. Taken together, these findings identified that HDAC11 may regulate SG formation to promote EndMT in atherosclerosis, targeting SG could represent a novel therapeutic strategy for addressing the underlying mechanisms of atherosclerosis.
组蛋白去乙酰化酶11（HDAC11）是IV类HDAC家族的唯一成员，与心血管疾病（CVD）相关。应激颗粒（SG）是由各种应激条件诱导形成的无膜细胞质聚集体，也是心血管疾病的关键因素。然而，HDAC11在动脉粥样硬化过程中对SG形成的调控作用及其潜在机制仍不清楚。因此，我们旨在研究HDAC11对高脂饮食喂养的ApoE小鼠和过氧化氢（HO）诱导的人脐静脉内皮细胞（HUVECs）中SG的影响。首先，通过蛋白质免疫印迹、实时荧光定量PCR和免疫荧光染色分析，我们发现高脂饮食喂养12周的ApoE小鼠主动脉中SG核心蛋白G3BP1/2和HDAC11的表达水平升高。此外，ApoE小鼠主动脉发生了内皮-间充质转化（EndMT）。然后，体外实验表明，用HO处理HUVECs会导致SG形成、HDAC11上调和EndMT发生。此外，用小干扰RNA（siRNA）敲低HDAC11可显著减弱HO诱导的HUVECs中SG形成和EndMT激活。HDAC11沉默抑制了HO诱导的HUVECs中EndMT激活，这可能归因于G3BP1/2乙酰化增加以及随之而来的SG形成受损。进一步研究发现，抑制SG形成不仅促进了内皮标志物的表达，还降低了间充质细胞标志物的水平。综上所述，这些发现表明HDAC11可能通过调节SG形成来促进动脉粥样硬化中的EndMT，针对SG可能代表一种解决动脉粥样硬化潜在机制的新治疗策略。
