Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Atherosclerosis is characterized by the accumulation of lipid-laden macrophages in the arterial walls. Patients with inflammatory arthritis and psoriasis are at greater risk of developing atherosclerotic plaques with their associated cardiovascular diseases. Recent studies indicate that effective therapy of inflammatory arthritis may reduce the risk of atherosclerotic cardiovascular disease although the basis for this risk reduction is not totally clear. Recently apremilast, an inhibitor of PDE4, has been introduced into the clinical armamentarium for the treatment of psoriasis and inflammatory arthritis. We and others have recently demonstrated that agents, such as adenosine A2A receptor stimuli, that stimulate cAMP accumulation in macrophages can reduce foam cell formation by a protein kinase A (PKA) – mediated mechanism involving enhanced efflux of cholesterol and lipids. We therefore asked whether apremilast might have a similar effect
Methods: RAW264.7 murine macrophage cell line was infected with lentiviruses expressing shRNA to silence PKA, EPAC1 and EPAC2, or scrambled shRNA. Knockdown was confirmed by Western Blot. The effect of apremilast on foam cell formation was tested by examination of 70% confluent cells in 48-well plates following treatment with Interferon-γ (IFNγ, 0.5u/ul) for 24 hours and then treatment with acetylated LDL (50ug/ml) with/without apremilast (10uM) for another 48 hours. Cells were stained with oil-O-red and then cells containing lipid droplets were counted. To determine whether apremilast affected cholesterol efflux cells (70% confluent in 48-well plates) were treated with IFNγ (0.5u/ul) for 24 hours and followed by treatment with acLDL (50ug/ml) for another 24 hours. After treatment with bodipy-cholesterol for 1 hour, cells were cultured in the equilibration buffer for 18 hours and treated with HDL (20ug/ml) and ApoA1(10ug/ml with/without apremilast (AP, 10uM) for 4 hours. 200ul of each supernant /cell lysate (lysed in 1% cholic acid) were analyzed by record fluorescence @482/515nm.
Results: Apremilast treatment reduced foam cell formation in RAW264.7 cells stably expressing scrambled, EPAC1 and EPAC2, but not PKA shRNA (45±2%, 43±5%, 42±1% and -14±6% reduction, respectively, p<0.001, ANOVA). Apremilast treatment enhanced HDL-induced and apoA1-induced cholesterol efflux from RAW264.7 cells (2.345 ± 0.03% vs. 1.733 ± 0.08%, p<0.001, n=4 and 9.74 ± 0.32% vs.3.96±0.77%, p<0.05, n=3). Furthermore, Apremilast treatment enhanced HDL-induced from Raw264.7 cells stably expressing scrambled, EPAC1, and PKA but not in EPAC2 shRNA (0.737±0.6% vs.1.19±0.04% of control, p<0.05, ANOVA); apremilast treatment enhanced ApoA1-induced cholesterol efflux from RAW264.7 cells stably expressing scrambled, but not EPAC1, EPAC2, and PKA shRNA (2.62±0.15%, 1.55±0.22%, 1.44±0.04% a vs. 0.95±0.15% of control, respectively, p<0.01, p<0.05 and p<0.01, ANOVA). Thus, these results suggested that 1)apremilast promotes HDL-induced cholesterol efflux through increasing intracellular cAMP with EPAC1dependent mechanism, and apoA1-induced cholesterol efflux through increasing intracellular cAMP with EPAC1, EPAC2, PKA dependent mechanisms, 2) apremilast inhibits foam cell formation through increasing intracellular cAMP by only PKA-dependent mechanism
Conclusion: These results suggest that apremilast may be useful for the treatment/prevention of atherosclerosis in patients with psoriasis and inflammatory arthritis.
To cite this abstract in AMA style:Liu H, Wilder T, Mediero A, Wei Z, Corciulo C, Cronstein B. Apremilast May Improve Atherosclerosis By Promoting Cholesterol Efflux and Inhibiting Foam Cell Formation in Atherosclerotic Plaques [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/apremilast-may-improve-atherosclerosis-by-promoting-cholesterol-efflux-and-inhibiting-foam-cell-formation-in-atherosclerotic-plaques/. Accessed November 30, 2020.
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