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

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.

Sulfiredoxin-1 Inhibits PDGF-BB-Induced Vascular Smooth Muscle Cell Proliferation and Migration by Enhancing the Activation of Nrf2/ARE Signaling.

Sulfiredoxin1 (Srxn1), an endogenous antioxidant protein, is involved in cardiovascular diseases. In this study, we aimed to investigate the role of Srxn1 in VSMCs and its molecular mechanism. The murine vascular smooth muscle cells MOVAS were treated with different doses of platelet-derived growth factor-BB (PDGF-BB); then, Srxn1 expression was detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. MTT and wound healing assay were used to examine the effect of Srxn1 on MOVAS cell proliferation and migration. Reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity in MOVAS cells were detected using corresponding commercial kits. Moreover, the expression of proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2), and nuclear factor erythroid-2-related factor 2 (Nrf2) /antioxidant response element (ARE) signaling-related proteins was detected using western blot analysis. In our study, PDGF-BB dose-dependently increased Srxn1 expression in MOVAS cells, and Srxn1 expression was increased with time dependence in PDGF-BB-treated MOVAS cells. The knockdown of Srxn1 increased PDGF-BB-induced the proliferation, migration, ROS production, MDA level, and the protein expression of PCNA and MMP-2, as well as decreased SOD activity and the expression of Nrf2/ARE signaling-related proteins in PDGF-BB-stimulated MOVAS cells. However, the overexpression of Srxn1 showed the opposite results to those of knockdown of Srxn1. Moreover, the inhibitory effects of Srxn1 overexpression on PDGF-BB induced proliferation, migration, ROS production, and MDA level and the promotion of Srxn1 overexpression on PDGF-BB induced SOD activity were partially reversed by the knockdown of Nrf2. Srxn1 inhibited PDGF-BB-induced proliferation, migration, and oxidative stress through activating Nrf2/ARE signaling.