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Niclosamide downregulates LOX-1 expression in mouse vascular smooth muscle cells and changes the composition of atherosclerotic plaques in ApoE−/− mice

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Abstract

Genetic lineage tracing studies have shown that phenotypic switching of vascular smooth muscle cells (VSMCs) results in less-differentiated cells, including macrophage-like cells that lack traditional VSMC markers. This switching contributes to the formation of necrotic core in plaques and promotes atherosclerosis, which is important for plaque stability. Niclosamide, a commonly used anti-helminthic drug, has recently attracted attention as an anti-cancer drug that inhibits multiple signaling pathways. The expression of the S100A4 protein is upregulated in synthetic VSMCs and inhibited by niclosamide on metastatic progression in colon cancer. We aimed to test the effect of niclosamide on VSMC phenotype switching and plaque stability. To examine murine atherosclerosis, we induced experimental lesions by blood flow cessation in apolipoprotein E knockout mice fed a high-fat diet. Oral administration of niclosamide changed 4-week-old plaques to collagen-rich and less-necrotic core phenotypes and downregulated the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in vivo. In vitro analysis indicated that niclosamide reduced LOX-1 expression in VSMCs in a concentration-dependent and S100A4-independent manner. The inhibitory effect of niclosamide on LOX-1 and collagen type I was associated with the inactivation of the nuclear factor-κB signaling pathway. We demonstrated that the administration of niclosamide reduced LOX-1 expression and altered the composition of murine carotid plaques. Our results highlight the potential of niclosamide as an atheroprotective agent that enhances atherosclerotic plaque stability.

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Abbreviations

VSMCs:

Vascular smooth muscle cells

LOX-1:

Lectin-like oxidized low-density lipoprotein receptor-1

NF-κB:

Nuclear factor-κB

SMA:

Smooth muscle actin

PL:

Partial ligation

CA:

Carotid artery

ApoE:

Apolipoprotein E

IEL:

Internal elastic lamina

MβCD:

Methyl-β-cyclodextrin

LPS:

Lipopolysaccharide

ox-LDL:

Oxidized low-density lipoprotein

ROS:

Reactive oxygen species

AMPK:

AMP-activated protein kinase

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Acknowledgements

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Funding

This work was supported in part by grants from the Japan Society for the Promotion of Science JSPS KAKENHI: Grants No. 26460338 and 17K08592 (to MM) and 15K10299 and 20K08446 (to KY).

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Authors and Affiliations

  1. Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogun, Sakyo-ku, Kyoto, 606-8507, Japan

    Tao Yang, Kazumichi Yoshida, Manabu Nagata, Yu Yamamoto, Naoki Takayama, Keita Suzuki, Takeshi Miyata, Masakazu Okawa & Susumu Miyamoto

  2. Department of Clinical Innovative Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogun, Sakyo-ku, Kyoto, 606-8507, Japan

    Tao Yang, Manabu Minami, Manabu Nagata, Yu Yamamoto & Takeshi Miyata

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  1. Tao Yang
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Yang, T., Minami, M., Yoshida, K. et al. Niclosamide downregulates LOX-1 expression in mouse vascular smooth muscle cells and changes the composition of atherosclerotic plaques in ApoE−/− mice. Heart Vessels 37, 517–527 (2022). https://doi.org/10.1007/s00380-021-01983-z

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