2. Academic Validation
  3. Arsenic trioxide alleviates atherosclerosis by inhibiting CD36-induced endocytosis and TLR4/NF-κB-induced inflammation in macrophage and ApoE-/- mice

Arsenic trioxide alleviates atherosclerosis by inhibiting CD36-induced endocytosis and TLR4/NF-κB-induced inflammation in macrophage and ApoE-/- mice

  • Int Immunopharmacol. 2024 Jan 17:128:111452. doi: 10.1016/j.intimp.2023.111452.
Zhaoying Li 1,  Xiaoyi Zou 2,  Rongzhe Lu 1,  Xin Wan 3,  Song Sun 3,  Shanjie Wang 1,  Yinan Qu 4,  Yun Zhang 5,  Zhangyi Li 6,  Liming Yang 7,  Shaohong Fang 8
Affiliations

Affiliations

  • 1 Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, Heilongjiang Province, China.
  • 2 The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, Heilongjiang Province, China.
  • 3 The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, Heilongjiang Province, China; Department of Neurobiology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang Province, China.
  • 4 Department of Cardiac Function, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong Province, China.
  • 5 Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA.
  • 6 Department of biochemistry and life sciences, Faculty of Arts and Sciences, Queen's University, Kingston, Ontario, Canada.
  • 7 Department of Pathophysiology, Harbin Medical University, Harbin, Heilongjiang Province, China. Electronic address: limingyanghmu@163.com.
  • 8 Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; National Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical University, Harbin, Heilongjiang Province, China. Electronic address: fangshaohong7802@163.com.
PMID: 38237221 DOI: 10.1016/j.intimp.2023.111452
Abstract

Background: Inflammation and lipid accumulation are key events in atherosclerosis progression. Despite arsenic trioxide's (ATO) toxicity, at appropriate doses, it is a useful treatment for various diseases treatment. ATO prevents vascular restenosis; however, its effects on atherosclerotic plaque development and instability remain unclear.

Methods: ApoE-/- mice were fed high-fat diet for 4 months, and starting at the third month, ATO was intravenously administered every other day. Atherosclerotic lesion size, histological characteristics, and related protein and lipid profiles were assessed using samples from the aorta, carotid artery, and serum. The anti-inflammatory and anti-pyroptosis effects of ATO were investigated by stimulating RAW264.7 and THP-1 cell lines with oxidized low-density lipoprotein (ox-LDL) or lipopolysaccharide (LPS).

Results: ATO reduced atherosclerotic lesion formation and plasma lipid levels in ApoE-/- mice. In the serum and aortic plaques, ATO reduced the levels of pro-inflammatory factors, including interleukin (IL) 6 and tumor necrosis factor α, but increased IL-10 levels. Mechanistically, ATO promoted the CD36-mediated internalization of ox-LDL in a Peroxisome Proliferator-activated Receptor γ-dependent manner. Furthermore, ATO downregulated Toll-like Receptor 4 (TLR4) expression in plaques and macrophages and inhibited p65 nuclear translocation and IκBα degradation. ATO reduced macrophage Pyroptosis by downregulating NLR family pyrin domain-containing 3 (NLRP3) expression and Caspase 1 activation.

Conclusion: ATO has potential atheroprotective effects, especially in macrophages. The mechanisms were inhibition of CD36-mediated foam cell formation and suppression of inflammatory responses and Pyroptosis mediated by TLR4/nuclear factor κB and NLRP3 activation. Our findings provide evidence supporting the potential atheroprotective value of ATO.

Keywords

Arsenic trioxide; Inflammation; Macrophage; Pro-inflammatory cytokine.

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