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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: March 01, 2019
Accepted:
February 20,
2019
Received in revised form:
February 17,
2019
Received:
July 16,
2018
Identification
Copyright
© 2019 Elsevier B.V. All rights reserved.
