Gang Wang1, Jia-Hui Gao1, Lin-Hao He2, Xiao-Hua Yu1, Zhen-Wang Zhao1, Jin Zou1, Feng-Jiao Wen2, Li Zhou1, Xiang-Jun Wan1, Chao-Ke Tang3. 1. Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic disease, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China. 2. School of Pharmacy and Life Science College, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. 3. Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic disease, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.. Electronic address: tangchaoke@qq.com.
Abstract
BACKGROUND AND AIMS: Fargesin mainly functions in the improvement of lipid metabolism and the inhibition of inflammation, but the role of fargesin in atherogenesis and the molecular mechanisms have not been defined. We aimed to explore if and how fargesin affects atherosclerosis by regulating lipid metabolism and inflammatory response. METHODS AND RESULTS: ApoE-/- mice were fed a high-fat diet to form atherosclerotic plaques and then administrated with fargesin or saline via gavage. Oil Red O, HE and Masson staining were performed to assess atherosclerostic plaques in apoE-/- mice. [3H] labeled cholesterol was used to detect cholesterol efflux and reverse cholesterol transport (RCT) efficiency. Enzymatic methods were performed to analyze plasma lipid profile in apoE-/- mice. Immunohistochemistry was used to analyze macrophage infiltration. THP-1-derived macrophages were incubated with fargesin or not. Both Western blot and qRT-PCR were applied to detect target gene expression. Oil Red O staining was applied to examine lipid accumulation in THP-1-derived macrophages. ELISA and qRT-PCR were used to examine the levels of inflammatory mediotors. We found that fargesin reduced atherosclerotic lesions by elevating efficiency of RCT and decreasing inflammatory response via upregulation of ABCA1 and ABCG1 expression in apoE-/- mice. Further, fargesin reduced lipid accumulation in THP-1-derived macrophages. Besides, fargesin increased phosphorylation of CEBPα in Ser21 and then upregulated LXRα, ABCA1 and ABCG1 expression in THP-1-derived macrophages. In addition, fargesin could reduce ox-LDL-induced inflammatory response by inactivation of the TLR4/NF-κB pathway. CONCLUSION: These results suggest that fargesin inhibits atherosclerosis by promoting RCT process and reducing inflammatory response via CEBPαS21/LXRα and TLR4/NF-κB pathways, respectively.
BACKGROUND AND AIMS: Fargesin mainly functions in the improvement of lipid metabolism and the inhibition of inflammation, but the role of fargesin in atherogenesis and the molecular mechanisms have not been defined. We aimed to explore if and how fargesin affects atherosclerosis by regulating lipid metabolism and inflammatory response. METHODS AND RESULTS:ApoE-/- mice were fed a high-fat diet to form atherosclerotic plaques and then administrated with fargesin or saline via gavage. Oil Red O, HE and Masson staining were performed to assess atherosclerostic plaques in apoE-/- mice. [3H] labeled cholesterol was used to detect cholesterol efflux and reverse cholesterol transport (RCT) efficiency. Enzymatic methods were performed to analyze plasma lipid profile in apoE-/- mice. Immunohistochemistry was used to analyze macrophage infiltration. THP-1-derived macrophages were incubated with fargesin or not. Both Western blot and qRT-PCR were applied to detect target gene expression. Oil Red O staining was applied to examine lipid accumulation in THP-1-derived macrophages. ELISA and qRT-PCR were used to examine the levels of inflammatory mediotors. We found that fargesin reduced atherosclerotic lesions by elevating efficiency of RCT and decreasing inflammatory response via upregulation of ABCA1 and ABCG1 expression in apoE-/- mice. Further, fargesin reduced lipid accumulation in THP-1-derived macrophages. Besides, fargesin increased phosphorylation of CEBPα in Ser21 and then upregulated LXRα, ABCA1 and ABCG1 expression in THP-1-derived macrophages. In addition, fargesin could reduce ox-LDL-induced inflammatory response by inactivation of the TLR4/NF-κB pathway. CONCLUSION: These results suggest that fargesin inhibits atherosclerosis by promoting RCT process and reducing inflammatory response via CEBPαS21/LXRα and TLR4/NF-κB pathways, respectively.
Authors: Dmitry I Osmakov; Aleksandr P Kalinovskii; Olga A Belozerova; Yaroslav A Andreev; Sergey A Kozlov Journal: Int J Mol Sci Date: 2022-05-27 Impact factor: 6.208