Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells

Abstract

Background: Oxidized low-density lipoprotein (oxLDL) induced a foam-cell like phenotype of the vascular smooth muscle cells (VSMCs), leading to the inflammatory responses incorporating Toll-like receptors (Tlrs)-mediated cellular alterations. We previously found that Tlr4 participated in inflammation response in VSMCs under oxLDL stimulation. However, the role of Tlr4 in foam-cell formation and underlying molecular pathways has not been comprehensively elucidated. This study aimed to investigate the role of Tlr4-mediated mechanisms in oxLDL induced foam-cell formation within VSMCs. Methods: After incubated with different dose of oxLDL, the lipid, reactive oxygen species (ROS) accumulation and foam-cell phenotype of the VSMCs were detected. The alteration of Tlr family, ROS and lipid accumulation regulators including the Src kinase, Nox2, Nox4, Mnsod and sirtuins were measured. Then the Tlr4 was knock down and underlying cellular change and altered molecules were detected. Results: We showed that oxLDL induced foam-cell like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. OxLDL induced the strongest upregulation of Tlr4 in the Tlrs family and initiated change of Src activation, Nox2, Mnsod, sirt1 and sirt3 expression. The effect of oxLDL was abolished by Tlr4 knockdown. Furthermore, knocking down of Tlr4 reduced Src activation and led to restored Sirt1/Sirt3 expression. Moreover, inhibiting or knocking down the Src kinase diminished lipid accumulation in VSMCs under oxLDL treatment. And overexpression of Sirt1/3 relieved the oxLDL induced ROS accumulation and foam-cell phenotype in VSMCs.Conclusions: These results demonstrated that Tlr4 is a critical regulator in oxLDL induced foam cell formation of VSMCs via mediating Src kinase as well as Sirt1 and Sirt3. Beyond the role of Tlr4 in inflammation response of VSMCs, we provide an integrated mechanism about TLR4 in VSMCs phenotype transition under oxLDL stimulation.

Anti-atherosclerotic effects of genistein in preventing ox-low-density lipoprotein-induced smooth muscle-derived foam cell formation via inhibiting SRC expression and L-Ca channel currents

“…This finding is partially supported by a report by Lee et al that genistein obviously decreased SRC phosphorylation in prostate cancer cells (38). A recent report unveiled that repressing SRC activation attenuated ox-LDL-induced lipid accumulation and foam cell formation in VSMCs (39). Concordantly, Lang et al demonstrated that the downregulation of SRC correlated to the reduced proliferation and migration of hydrogen peroxide-exposed VSMCs (40).…”

Down-Regulation of Toll-Like Receptor 5 (TLR5) Increased VEGFR Expression in Triple Negative Breast Cancer (TNBC) Based on Radionuclide Imaging

“…VEGF and its receptor VEGFR played an important role in the development of TNBC, and VEGFR was mainly taken as the target and VEGF121, which had a high affinity with VEGFR, seemed to be an ideal tracer (33). It was reported that down-regulation of TLR5 expression could promote proliferation, invasion, and metastasis of TNBC, and TNBC overexpressed VEGF and VEGFR (34). In this study, we confirmed that the expression of VEGFR in 4T1 cells was increased when the expression of TLR5 was down-regulated, suggesting that the down-regulation of TLR5 had an influence on the increase of angiogenesis.…”