Eastern Regional Meeting - 2008 Program & Abstracts
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ATHEROGENICITY OF COX INHIBITION IS ENHANCED IN THE PRESENCE OF LUPUS SERUM AND ABROGATED BY PROSTAGLANDIN D2 OR E2
S. Edelman, E. Pone, S. Carsons, E. Belilos, L. Bonetti, K. Belostocki, G. Rosenblum, A.B. Reiss, Rheumatology, Winthrop University Hospital, Mineola, NY; E.S. Chan, Rheumatology, New York University, New York, NY
Purpose of Study: Atherosclerotic cardiovascular (CV) disease is a major cause of mortality in systemic lupus erythematosus (SLE). The heightened inflammatory state in SLE leads to elevated levels of immune reactants which, in turn, accelerate foam cell formation, a key event in atherosclerosis. Cyclooxygenase (COX) inhibiting medications alleviate pain and inflammation in SLE and other conditions, but increase CV risk. We reported that inhibition of COX-1 and/or COX-2 increases foam cell formation in THP-1 human macrophages under conditions of cholesterol loading. We hypothesize that exposure of THP-1 macrophages to SLE serum will further aggravate foam cell transformation in the presence of COX inhibitors; specific PGs may reverse this effect.
Methods Used: THP-1 macrophages (106/ml, phorbol dibutyrate) +12h pre-incubation in 50% SLE serum, were incubated(18h)+10µM NS-398 (COX-2 inhibitor) or +0.001µM SC560 (COX-1 inhibitor), then with acLDL(50 µg/ml) under 4 conditions: control, PGD2 (5 µg/ml), PGE2 (10-7 M), PGI2 (10-7 M). Foam cells were quantified as %oil red O stained cells.
Summary of Results: SLE serum alone did not significantly impact foam cell formation compared to control (42.8+5.3% vs. 50.7+1.7%, p=NS). COX-1 or COX-2 inhibition in the presence of SLE serum increased foam cell transformation significantly compared to SLE serum alone (62.6+1.1%, 82.7+2.8 % vs. 42.8+5.3%, respectively, p<0.001). Addition of PGD2 or PGE2 significantly reversed either NS-398 or SC560-induced foam cell transformation in the presence of SLE serum. PGI2 did not affect macrophage foam cell transformation.
Conclusions: In THP-1 macrophages, COX inhibition increases vulnerability to lipid overload and foam cell formation in the SLE serum milieu. This vulnerability is reversed (even in the presence of SLE serum) by PGD2 or PGE2 but not by PGI2. The atherogenicity of COX inhibition may be augmented by inflammatory mediators in SLE serum, posing an exaggerated risk to SLE patients treated with COX inhibitors. Notably, disrupted cholesterol balance may be corrected by specific PGs, suggesting possible future therapeutic modalities for COX inhibition that would support an anti-atherogenic PG state.
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