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Celecoxib aggravates atherogenesis and upregulates leukotrienes in ApoE−/− mice and lipopolysaccharide-stimulated RAW264.7 macrophages

  • Author Footnotes
    1 These three authors contributed equally to this work.
    Yimin Pang
    Footnotes
    1 These three authors contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021,Guangxi, China
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  • Author Footnotes
    1 These three authors contributed equally to this work.
    Lu Gan
    Footnotes
    1 These three authors contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021,Guangxi, China
    Search for articles by this author
  • Author Footnotes
    1 These three authors contributed equally to this work.
    Xianzhe Wang
    Footnotes
    1 These three authors contributed equally to this work.
    Affiliations
    Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021,Guangxi, China
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  • Qi Su
    Affiliations
    Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021,Guangxi, China
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  • Cong Liang
    Affiliations
    Department of Pharmacology, School of Pharmacy, Guangxi Medical University, Nanning 530021,Guangxi, China
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  • Ping He
    Correspondence
    Corresponding author. Laboratory Animal Center, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, China. Tel.: +86 13607864525.
    Affiliations
    Laboratory Animal Center, Guangxi Medical University, Nanning 530021, Guangxi, China
    Search for articles by this author
  • Author Footnotes
    1 These three authors contributed equally to this work.

      Highlights

      • The COX-2-selective inhibitor celecoxib aggravates atherogenesis but has no effect on hyperlipidemia.
      • Leukotrienes are upregulated in the celecoxib-treated atherosclerosis (AS) model.
      • Leukotrienes upregulation is due to the a 5-LO pathway shunt in the celecoxib-treated AS model.

      Abstract

      Background and aims

      COX-2-selective inhibitors have been associated with an increased risk of cardiovascular complications, and their impact on atherosclerosis (AS) remains controversial. The proinflammatory COX-2 and 5-LO pathways both play essential roles in AS and related cardiovascular diseases. Previous clinical studies have provided evidence of the ability of COX-2-selective inhibitors to shunt AA metabolism from the COX-2 pathway to the 5-LO pathway. In this study, the effects of celecoxib, a selective COX-2 inhibitor, on AS and the COX-2 and 5-LO pathways were investigated in vivo and in vitro.

      Methods

      Male ApoE−/− mice fed a western-type diet for 18 weeks and cultured mouse RAW264.7 macrophages stimulated with 1 μg/mL LPS for 24 h were used in this study.

      Results

      In ApoE−/− mice, intragastric administration of celecoxib (80 mg/kg/d) for 18 weeks significantly increased aortic atherosclerotic lesion area but had no effect on hyperlipidemia. In addition, celecoxib significantly lowered TNF-α and PGE2 levels but increased both LTB4 and CysLTs levels in aortic tissues. In LPS-stimulated RAW264.7 macrophages, pretreatment with 8 μmol/L celecoxib for 1 h significantly lowered the TNF-α, NO, and PGE2 levels but increased the LTB4 and CysLTs levels. Celecoxib also decreased the protein and mRNA expression of COX-2 but increased the expression of 5-LO and LTC4S in both ApoE−/− mouse aortic tissues and LPS-stimulated RAW264.7 macrophages.

      Conclusion

      The COX-2-selective inhibitor celecoxib can aggravate atherogenesis, an effect that may be related to upregulation of LTs via a 5-LO pathway shunt.

      Keywords

      Abbreviations:

      AS (atherosclerosis), COX-2 (cyclooxygenase-2), 5-LO (5-lipoxygenase), LTs (leukotrienes), LTB4 (leukotriene B4), LTC4S (LTC4 synthase), CysLTs (cysteinyl leukotrienes), ApoE (apolipoprotein E), LPS (lipopolysaccharide), TG (total triglyceride), TC (total cholesterol), LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), TNF-α (tumor necrosis factor-α)
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