1. Academic Validation
  2. Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway

Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway

  • Eur J Pharmacol. 2020 Oct 5;884:173408. doi: 10.1016/j.ejphar.2020.173408.
Lin-Hao He 1 Jia-Hui Gao 2 Xiao-Hua Yu 2 Feng-Jiao Wen 2 Jing-Jing Luo 1 Yu-Sheng Qin 2 Ming-Xin Chen 1 Da-Wei Zhang 3 Zong-Bao Wang 4 Chao-Ke Tang 5
Affiliations

Affiliations

  • 1 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China; School of Pharmaceutical Science, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, 421001, China.
  • 2 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China.
  • 3 Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
  • 4 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China; School of Pharmaceutical Science, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
  • 5 Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
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-/- 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.

Keywords

Artesunate; Atherosclerosis; KLF2; LPL; NRF2; TCF7L2.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-19543
    99.89%, Nrf2 Inhibitor