Histone deacetylase 11 regulates stress granule formation to promote endothelial-to-mesenchymal transition in atherosclerosis.

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.