Purpose of Study It is the second decade of controversy regarding the cardiovascular (CV) effects of cycloxygenase-2 (COX-2) inhibitors. COX-2 inhibitors possess anti-inflammatory and analgesic effects comparable with conventional non-steroidal anti-inflammatory drugs, but produce fewer gastrointestinal adverse effects. Here we demonstrate that only selective COX-2 inhibitors cause disruption of the delicate balance between cholesterol efflux and influx that leads to lipid overload and macrophage foam cell formation (FCF).
Methods Used THP-1 human macrophages were incubated with: celecoxib (10 µM, 25 µM); rofecoxib (10 µM, 25 µM); naproxen (10 µM, 25 µM); acetaminophen (0.5 mM, 1 mM)±oxidized low density lipoprotein (oxLDL, 25 µg/ml, 48 h) or 5 µg/ml (Dil)-oxLDL. FCF (% oil red O stained cells) and oxLDL accumulation were determined (fluorescent intensity). Scavenger receptors: CD36, LOX-1, SR-A1 and CXCL16 and cholesterol efflux proteins: ATP-binding cassette transporter (ABC) A1 and ABCG1 were detected in macrophages by QRT-PCR and immunocytochemistry.
Summary of Results Celecoxib decreased ABCA1 and ABCG1 message in a concentration dependent manner: 68.2±13.36% for ABCA1 and 65.7±13.36% for ABCG1 (control set at 100%, n=6, P<0.01). Neither naproxen nor acetaminophen significantly affected expression of cholesterol efflux proteins. Both specific and nonspecific COX-2 inhibitors had a significant impact on expression of scavenger receptors CD36, LOX-1 and SR-A1–nearly double control (n=6, P<0.05). However, only specific COX-2 inhibitors significantly increased FCF in THP-1 differentiated macrophages (62.2±5.2% for celecoxib and 56.3±3.4% for rofecoxib vs. 33.5±5.1% for untreated cells, P<0.05).
Conclusions Here we report that only specific COX-2 inhibitors might contribute to atherogenesis by promoting lipid overload and lipoprotein accumulation. This may explain, in part, the increased CV risk in patients taking COX-2 inhibitors for extended periods. Despite increased scavenger receptor expression, naproxen and acetaminophen do not impact lipid content, perhaps because efflux pathways remain intact.
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