Chen Xue,Kang Yulai,Tang Chunhua,Zhang Lili,Guo Lu
Foam cells are primarily formed through scavenger receptors that mediate the uptake of various modified low-density lipoproteins (LDL) into cells. In addition to the receptor-dependent pathway, macropinocytosis is an essential non-receptor endocytic pathway for vascular smooth muscle cells (VSMCs) to take up lipids. However, the molecular mechanisms underlying this process remain unclear. Primary cultured VSMCs were stimulated with 200 ng/ml lipopolysaccharide (LPS) and 200 μg/ml native LDL (nLDL). We observed a significant increase in TLR4 protein expression and a significant activation of macropinocytosis, which correlated with the highest uptake of nLDL and intracellular lipid deposition in WT VSMCs. However, macropinocytosis was inhibited and lipid accumulation decreased after treatment with macropinocytosis inhibitors and Syk inhibitors in WT VSMCs. Consistently, TLR4 knockout significantly suppressed macropinocytosis and lipid droplets accumulation in VSMCs. Taken together, our findings suggest a critical role of TLR4/Syk signaling in promoting receptor-independent macropinocytosis leading to VSMC-derived foam cells formation.
Aims Y-box protein 1 (YB1) is a key regulator of inflammatory mediators . However, the roles of YB1 in oxidized low-density lipoprotein (ox-LDL)-induced macrophage inflammation and lipid uptake remain less understood. Thus, we explored the roles of YB1 in ox-LDL-induced macrophage inflammation and lipid uptake and its underlying molecular mechanisms. Methods An ox-LDL-induced atherosclerosis (AS) model was used in this study. Western blotting , RT-PCR, immunofluorescence, ELISA, dil-ox-LDL staining, a dual-luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) and in vivo experiments were used to detect each target. Results ox-LDL downregulates YB1 expression in THP-1-derived macrophages and human monocyte-derived macrophages (hMDMs) via the NF-κB pathway. Downregulation of YB1 is facilitated by lipid uptake in macrophages, and CD36 is involved in this process. Furthermore, YB1 suppresses CD36 protein levels by directly binding to the coding sequence of the CD36 gene to promote CD36 mRNA decay but does not affect its mRNA transcription. Additionally, YB1 knockdown enhances the inflammatory response and lipid deposition via the NF-κB pathway in vivo. Conclusion ox-LDL decreases YB1 expression in macrophages, resulting in enhanced inflammatory responses by affecting NF-κB and facilitating lipid uptake by promoting scavenger receptor CD36 mRNA decay.
Reducing lipid uptake of macrophages and stimulating cholesterol efflux are two necessary steps for atherosclerotic plaque regression. In this study, a compound of curcumin nicotinate (CN) was synthesized from nicotinic acid which can raise raising high-density lipoprotein (HDL) and curcumin which can lower lipid. However, the shortcomings of CN, such as poor water solubility and low bioavailability, limit its clinical application. In this article, a CN loaded biomimetic nanosystem was constructed by using Prussian blue nanoparticles (PB NPs) to improve its solubility, thereby changing its administration route. In addition, hyaluronic acid (HA) modification on the biomimetic PB NPs was adopted to prolong circulation time and improve the accumulation of drugs in the plaque region. Mechanism studies have shown that the constructed nanosystem could exert anti-AS effects through the pathway of Proprotein Convertase Subtilisin/Kexin Type 9(PCSK9) /Low-density lipoprotein receptor (LDL-R), ATP Binding Cassette Transporter A1(ABCA1) /Caveolin-1 /Liver X Receptor (LXR). These findings indicated that the designed nano-platform is expected to be used for prevention and targeted therapy of atherosclerosis.
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