Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway
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 receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molec...
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| Language: | English |
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Wiley
2021-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2021/6639252 |
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| author | Zhongli Chen Qiqi Xue Lijuan Cao Yanpin Wang Yuanyuan Chen Xiaojie Zhang Fan Xiao Ying Yang Melvin R. Hayden Yan Liu Ke Yang |
| author_facet | Zhongli Chen Qiqi Xue Lijuan Cao Yanpin Wang Yuanyuan Chen Xiaojie Zhang Fan Xiao Ying Yang Melvin R. Hayden Yan Liu Ke Yang |
| author_sort | Zhongli Chen |
| collection | DOAJ |
| description | 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 receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molecular pathways has not been comprehensively elucidated. To further investigate the mechanism, VSMCs were incubated with different doses of oxLDL, and then, the lipid, reactive oxygen species (ROS) accumulation, Tlr family genes, and the foam cell phenotype were explored. We observed that oxLDL induced foam cell-like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. Furthermore, in the Tlr family, Tlr4 demonstrated the strongest upregulation under oxLDL stimulation. Simultaneously, oxLDL induced activation of Src, higher expression of Nox2, and lower expression of Mnsod, Sirt1, and Sirt3. By interfering the TLR4 expression, the phenotype alteration, lipid accumulation in VSMCs, and Src kinase activation induced by oxLDL were abolished. After interfering Src activation, the oxLDL-induced lipid accumulation and foam cell phenotype in VSMCs were also alleviated. Furthermore, the ROS accumulation, upregulated Nox2 expression, downregulated Sirt1, Sirt3, and Mnsod expression in VSMCs under oxLDL stimulation were also relieved after the knockdown of Tlr4. Additionally, overexpression of Sirt1 and Sirt3 ameliorated the ROS accumulation and foam cell-like marker expression in VSMCs. These results demonstrated that beyond its familiar role in regulating inflammation response, Tlr4 is a critical regulator in oxLDL-induced foam cell formation in VSMCs via regulating Src kinase activation as well as Sirt1 and Sirt3 expression. |
| format | Article |
| id | doaj-art-29cc00efa0d44020b40baf3b07e053d7 |
| institution | OA Journals |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-29cc00efa0d44020b40baf3b07e053d72025-08-20T02:04:01ZengWileyMediators of Inflammation0962-93511466-18612021-01-01202110.1155/2021/66392526639252Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 PathwayZhongli Chen0Qiqi Xue1Lijuan Cao2Yanpin Wang3Yuanyuan Chen4Xiaojie Zhang5Fan Xiao6Ying Yang7Melvin R. Hayden8Yan Liu9Ke Yang10Department of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, ChinaDepartment of Geratology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, ChinaDepartment of Cardiology, Huangpu Branch, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, ChinaDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, ChinaDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, ChinaDepartment of Electrocardiogram, Zhongshan Hospital, Fudan University, Shanghai 200032, ChinaDepartment of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, ChinaDepartment of Endocrinology, The Second People’s Hospital of Yunnan Province, Kunming, Yunnan 650021, ChinaDepartments of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Center, University of Missouri-Columbia School of Medicine, Columbia, 65201 Missouri, USADepartment of Cardiology, Shanghai Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, ChinaDepartment of Vascular & Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, ChinaOxidized 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 receptor- (Tlr-) mediated cellular alterations. However, the role of Tlr4 in foam cell formation and underlying molecular pathways has not been comprehensively elucidated. To further investigate the mechanism, VSMCs were incubated with different doses of oxLDL, and then, the lipid, reactive oxygen species (ROS) accumulation, Tlr family genes, and the foam cell phenotype were explored. We observed that oxLDL induced foam cell-like phenotype in VSMCs and led to lipid and ROS accumulation in a dose-dependent manner. Furthermore, in the Tlr family, Tlr4 demonstrated the strongest upregulation under oxLDL stimulation. Simultaneously, oxLDL induced activation of Src, higher expression of Nox2, and lower expression of Mnsod, Sirt1, and Sirt3. By interfering the TLR4 expression, the phenotype alteration, lipid accumulation in VSMCs, and Src kinase activation induced by oxLDL were abolished. After interfering Src activation, the oxLDL-induced lipid accumulation and foam cell phenotype in VSMCs were also alleviated. Furthermore, the ROS accumulation, upregulated Nox2 expression, downregulated Sirt1, Sirt3, and Mnsod expression in VSMCs under oxLDL stimulation were also relieved after the knockdown of Tlr4. Additionally, overexpression of Sirt1 and Sirt3 ameliorated the ROS accumulation and foam cell-like marker expression in VSMCs. These results demonstrated that beyond its familiar role in regulating inflammation response, Tlr4 is a critical regulator in oxLDL-induced foam cell formation in VSMCs via regulating Src kinase activation as well as Sirt1 and Sirt3 expression.http://dx.doi.org/10.1155/2021/6639252 |
| spellingShingle | Zhongli Chen Qiqi Xue Lijuan Cao Yanpin Wang Yuanyuan Chen Xiaojie Zhang Fan Xiao Ying Yang Melvin R. Hayden Yan Liu Ke Yang Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway Mediators of Inflammation |
| title | Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway |
| title_full | Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway |
| title_fullStr | Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway |
| title_full_unstemmed | Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway |
| title_short | Toll-Like Receptor 4 Mediated Oxidized Low-Density Lipoprotein-Induced Foam Cell Formation in Vascular Smooth Muscle Cells via Src and Sirt1/3 Pathway |
| title_sort | toll like receptor 4 mediated oxidized low density lipoprotein induced foam cell formation in vascular smooth muscle cells via src and sirt1 3 pathway |
| url | http://dx.doi.org/10.1155/2021/6639252 |
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