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

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 mu g/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-a and PGE2 levels but increased both LTB4 and CysLTs levels in aortic tissues. In LPS-stimulated RAW264.7 macrophages, pretreatment with 8 mu mol/L celecoxib for 1 h significantly lowered the TNF-a, 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 LPSstimulated 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.