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Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway.
- Source :
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European journal of pharmacology [Eur J Pharmacol] 2020 Oct 05; Vol. 884, pp. 173408. Date of Electronic Publication: 2020 Jul 31. - Publication Year :
- 2020
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Abstract
- Lipoprotein lipase (LPL) plays a central role in hydrolyzing triglyceride and its deficiency leads to atherosclerosis. Artesunate (ART), a derivative of artemisinin, has been demonstrated that ART reduces the formation of atherosclerotic plaques. However, it remains unclear whether ART-alleviated atherosclerotic lesion is involved in regulating lipid metabolism. ApoE <superscript>-/-</superscript> mice were fed a high-fat diet to form atherosclerotic plaques and then injected with artesunate or not. Oil Red O, HE and Masson staining were performed to assess atherosclerotic plaques. Both Western blot and qRT-PCR were applied to detect protein expression. The Luciferase reporter gene and Chromatin immunoprecipitation assays were used to assess the interaction between proteins. Immunofluorescence assay was performed to show the localization of target proteins. In vitro, our data shown that ART increased LPL expression and inhibition of NRF2 blocked the binding of TCF7L2 to LPL promoter region in VSMCs. Downregulated Klf2 could decrease the nuclear enrichment of NRF2, TCF7L2 and LPL expression. In vivo, ART decreased atherosclerotic plaque formation and increased VSMC counts and LPL expression within atherosclerotic plaques. We observed the reduced tendency of serum lipids, and increased in serum LPL activity in mice. In support of vitro data, the markedly increased KLF2, TCF7L2 and LPL expression have been detected in aorta. Our study suggests that ART may be a novel therapeutic drug for inhibition of atherosclerotic plaque formation. The molecular mechanism may involve in upregulation of LPL expression via the KLF2/NRF2/TCF7L2 pathway in VSMCs.<br /> (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Aorta drug effects
Aorta enzymology
Aorta pathology
Atherosclerosis enzymology
Atherosclerosis genetics
Atherosclerosis pathology
Cells, Cultured
Diet, High-Fat
Disease Models, Animal
Kruppel-Like Transcription Factors genetics
Lipids blood
Lipoprotein Lipase genetics
Male
Mice, Knockout, ApoE
Muscle, Smooth, Vascular enzymology
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle enzymology
Myocytes, Smooth Muscle pathology
NF-E2-Related Factor 2 genetics
Plaque, Atherosclerotic
Signal Transduction
Transcription Factor 7-Like 2 Protein genetics
Up-Regulation
Artesunate pharmacology
Atherosclerosis prevention & control
Kruppel-Like Transcription Factors metabolism
Lipoprotein Lipase metabolism
Muscle, Smooth, Vascular drug effects
Myocytes, Smooth Muscle drug effects
NF-E2-Related Factor 2 metabolism
Transcription Factor 7-Like 2 Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 884
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32739175
- Full Text :
- https://doi.org/10.1016/j.ejphar.2020.173408