Cyclin G2 promotes the formation of smooth muscle cells derived foam cells in atherosclerosis via PP2A/NF-κB/LOX-1 pathway

Abstract

Background: To investigate the role and underlying mechanism of cyclin G2 (G2-type cyclin) in the formation of vascular smooth muscle cells (VSMCs) derived foam cells. Methods:The levels of α-SMA (alpha-SM-actin), p-NF-κB (phosphorylation nuclear transcription factors kappa B), and LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) were measured by immunohistochemistry and western blotting. The mouse aortic root smooth muscle cell line MOVAS was transfected to over-express cyclin G2, which were then stimulated with 80 μg/mL ox-LDL (oxidized lowdensity lipoprotein) to induce foam cell formation. DT-061 an activator of PP2A (protein phosphatase 2A) agonist was used to verify the role of PP2A in the process.Results: Knocking out the Ccng2 gene in Apoe -/mice alleviated aortic lipid plaque, foam cell formulation, ameliorative body weight, and LDL-cholesterol. We observed that the number of α-SMA positive cells was significantly decreased in Apoe -/-Ccng 2-/mice compared to Apoe -/mice. Also, the protein levels of p-NF-κB and LOX-1 were markedly reduced in the aortic root of Apoe -/-Ccng2 -/mice. Upon stimulation with ox-LDL, upregulated cyclin G2 increased the intracellular lipid accumulation in MOVAS cells. Also, it suppressed the activity of PP2A but up-regulated LOX-1. Additionally, the cell nuclear translocation of p-NF-κB was increased. Interestingly, DT-061 intervention, re-activating the activity of PP2A, reduced the levels of nuclear p-NF-κB and LOX-1. This led to decreased lipid endocytosis reducing the formation of VSMCsderived foam cells.Conclusions: Cyclin G2 increases the nuclear translocation of p-NF-κB by reducing the enzymatic activity of PP2A and upregulating LOX-1, thereby promotes the formation of VSMCs -derived foam cells in atherosclerosis.

Cyclin G2 in macrophages triggers CTL-mediated antitumor immunity and antiangiogenesis via interferon-gamma

“…Protein phosphatase 2 phosphatase activator (PP2A) was previously shown to attenuate IFN-γ-induced STAT1 phosphorylation [13][14][15]; cyclin G2 interacts with PP2Ac to affect its function [37][38][39]. Accordingly, we examined whether PP2Ac was involved in the change in STAT1 nuclear content in macrophages after cyclin G2 knockdown.…”

The role and mechanism of tetramethylpyrazine for atherosclerosis in animal models: A systematic review and meta-analysis

“…During the recruitment of white blood cells from the bloodstream to the intima of the vessel, Icam-1 primarily acts as an integrin receptor, whereas MCP-1 helps recruit monocytes [ 35 ]. The pro-inflammatory cytokines induce the expression of ICAM-1, MCP-1, LOX-1, and 5-LOX and convert macrophages and smooth muscle cells into foam cells to form atherosclerotic plaques [ 39 ]. Additionally, these pro-inflammatory processes mediated by OX-LDL and LOX1 are thought to result in enlargement of lipid cores, rupture of lesions, and instability of arterial thrombosis [ 40 ].…”

Protein Phosphatase 2A Deficiency in Macrophages Increases Foam Cell Formation and Accelerates Atherosclerotic Lesion Development

“…Studies from Chen et al showed that PP2A deactivates eNOS by removing S1177 residue phosphorylation and reduces NO bioavailability ( 23 ). Zhang et al reported that PP2A activation using a PP2A activator DT-061 reduced the uptake and accumulation of lipids in mouse aortic vascular smooth muscle cells ( 24 ). Campbell et al and Yang found that decreased PP2A activity enhances the migration of vascular smooth muscle cells ( 25 , 34 ).…”