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1: COMPARATIVE EFFECT OF SELECTIVE AND NON-SELECTIVE COX-2 INHIBITORS ON LIPID ACCUMULATION IN HUMAN MACROPHAGES
  1. LJ Kasselman1,3,*,
  2. I Voloshyna1,3,
  3. MJ Littlefield1,3,
  4. N Siegart1,3,
  5. SE Carsons1,2,
  6. I Gomolin1,
  7. J De Leon1,3,
  8. AB Reiss1,3
  1. 1Department of Medicine, Winthrop University Hospital, Mineola, NY, United States
  2. 2Rheumatology and Allergy, Winthrop University Hospital, Mineola, NY, United States
  3. 3Winthrop Research Institute, Winthrop University Hospital, Mineola, NY, United States

    Abstract

    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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