PCSK9 inhibitor attenuates atherosclerosis by regulating SNHG16/EZH2/TRAF5‐mediated VSMC proliferation, migration, and foam cell formation

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor has been demonstrated to exert a great cardioprotection in cardiometabolic impairments, including atherosclerosis. However, its underlying mechanism remains not fully understood. This study focuses on uncovering the actions of PCSK9 inhibitor on the connection between atherosclerosis and vascular smooth muscle cell (VSMC) behaviors. qRT‐PCR was utilized to detect the expression of SNHG16. Proliferation and migration of VSMC were characterized by Cell Counting Kit‐8 and wound healing assays. The intracellular lipids and foam cell formation were assessed by Oil Red O staining, fluorescence image, and cholesterol quantification kit. Atherosclerosis in vivo was evaluated by imaging the atherosclerotic lesions, hematoxylin‐eosin staining, Oil Red O staining and Masson staining. The interaction between SNHG16 with EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) were investigated by fluorescence in situ hybridization, RNA immunoprecipitation, and chromatin immunoprecipitation assays. A ApoE−/− mice model was used to validate the role of PCSK9 inhibitor and SNHG16 for atherosclerosis. The protective regulation of PCSK9 inhibitor was observed both in high‐fat diet (HFD)‐fed mice and oxidized low‐density lipoprotein (ox‐LDL)‐treated VSMC, as manifested in the decreased the atherosclerotic lesions in vivo, as well as the weakened cell proliferation, migration, and formation of foam cells in vitro. SNHG16 was identified to be a downstream effector of PCSK9 inhibitor‐mediated biological functions, of which knockdown also significantly ox‐LDL‐treated VSMC proliferation, migration, and foam cell formation abilities. SNHG16 epigenetically suppressed TRAF5 via recruiting EZH2. Silencing of TRAF5 abolished the protective effects of SNHG16 knockdown on the pathogenesis of atherosclerosis. Collectively, PCSK9 inhibitor attenuated atherosclerosis by regulating SNHG16/EZH2/TRAF5 axis to impair the proliferation, migration, and foam cell formation of VSMC.

Role of EZH2-mediated epigenetic modification on vascular smooth muscle in cardiovascular diseases: A mini-review

“…Inhibition of EZH2 by UNC1999 significantly suppressed PDGF-BB-induced VSMC proliferation and neointima formation ( Liu et al, 2020 ). In another study, PCSK9 inhibitor PEP2-8 trifluoracetate attenuates AS by regulating SNHG16/EZH2/TRAF5-mediated VSMC proliferation, migration and foam cell formation ( Liu et al, 2023 ). Some EZH2 inhibitors, like DS-3201b, are in phase 2 clinical trials for solid tumors ( Izutsu et al, 2023 ).…”

“…Small nucleolar RNA Host Gene 16 (SNHG16), a downstream effector of PCSK9, promotes VSMC proliferation, migration, and foam cell formation, and this effect can be reversed by TNF receptor associated factor 5 (TRAF5). SNHG16 inhibits the reversal pathway of TRAF5 by recruiting EZH2, which promotes AS development ( Liu et al, 2023 ). Therefore, EZH2 plays a crucial role in SNHG16-mediated TRAF5-regulated VSMC proliferation, migration and foam cell formation pathway, further influencing AS progression.…”