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2011 Eastern Meeting Abstracts

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Scherly Leon1, 2, Iryna Voloshyna1, Michael Littlefield1, Allison B. Reiss1 1. Medicine, Winthrop University Hospital, Mineola, NY, United States. 2. Medicine, New York Hospital of Queens, Flushing, NY, United States.

Purpose of Study: Coxibs, a cyclooxygenase (COX)-2 inhibitors, are analgesic, anti-inflammatory agents. However, some of them possess cardiovascular toxicity. We demonstrated that coxibs suppress expression of cholesterol 27-hydroxylase (27-OHase) and ATP binding cassette transporter A1 (ABCA1), involved in reverse cholesterol transport (RCT). RCT proteins prevent lipid overload and macrophage foam cell formation (FCF). Here we report that exposure THP-1 macrophages to COX-2 specific inhibitors leads to cholesterol overload via disruption of cholesterol efflux and influx balance.

Methods Used: THP-1 macrophages were incubated for 18h in the presence or absence of a) celecoxib (5 µM); b) rofecoxib (5 µM); c) naproxen (5 µM); d) acetaminophen (1 mM). 1µg of total RNA was used per condition for QRT PCR. 27-OHase and ABCA1 were measured to assess cholesterol efflux. CD36 and LOX1 scavenger receptors were detected for analysis of cholesterol influx. THP-1 macrophages (phorbol dibutyrate, 100nM, 48 h) were exposed to oxLDL (25 µg/ml, 48h) at conditions described above. FCF was quantified as percentage oil red O stained cells. Studies were performed in triplicate.

Summary of Results: Incubation of THP-1 macrophages with specific coxibs decreased 27-OHase and ABCA1 message (by 30.2±7.1% and 24.6±5.6% of control, P<0.01 for celecoxib and by 35.6±10.7% and 26.0±7.1% of control, P<0.01 for rofecoxib). Nonspecific coxibs had no significant effect on these proteins. Specific and nonspecific coxibs, had a great impact on the expression of CD36 (150.0±20.4% for celecoxib; 167.4±8.78% for rofecoxib; 271.8±30.0% for naproxen; 171.7±18.9% for acetaminophen, P<0.05) and LOX1 (165.15±21.29% for celecoxib; 153.85±18.46% for rofecoxib; 178.1±10.18% for naproxen; 154.185±19.10% for acetaminophen, P<0.05). However, only exposure of THP-1 macrophages to specific coxibs had a significant increase in FCF (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: We report that coxibs affect cholesterol metabolism in THP-1 macrophages. However, only specific COX-2 inhibitors might contribute to atherogenesis by promoting lipid overload via disruption of the balance in the expression of cholesterol transport genes.

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