CHOLESTEROL 27-HYDROXYLASE BUT NOT APOLIPOPROTEIN apoE CONTRIBUTES TO A2A ADENOSINE RECEPTOR STIMULATED REVERSE CHOLESTEROL TRANSPORT

摘要

Movement of free cholesterol between the cellular compartment and acceptor is governed by cholesterol gradients that are determined by several enzymes and reverse cholesterol transport proteins. We have previously demonstrated that adenosine A2A receptors inhibit foam cell formation and stimulate production of cholesterol 27-hydroxylase (CYP27A1), an enzyme involved in the conversion of cholesterol to oxysterols. We therefore asked whether the effect of adenosine A2A receptors on foam cell formation in vitro are mediated by CYP27A1 or apoE, a carrier for cholesterol in the serum. We found that specific lentiviral siRNA infection markedly reduced apoE or 27-hydroxylase mRNA in THP-1 cells. Despite diminished apoE expression (p< 0.0002, IFNγ CGS vs. IFNγ alone, n= 4) CGS-21680, an adenosine A2A receptor agonist, inhibits foam cell formation. In contrast, CGS-21680 had no effect on reducing foam cell formation in CYP27A1 KD cells (4±2% p<0.5113 inhibition vs. IFNγ alone n= 4). Previously we reported the A2A agonist CGS-21680 increases apoAI-mediated cholesterol efflux nearly 2-fold in wildtype macrophages. Adenosine receptor activation had no effect on cholesterol efflux in CYP27A1 KD cells but reduced efflux in apoE KD cells. These results demonstrate that adenosine A2A receptor occupancy diminishes foam cell formation by increasing expression and function of CYP27A1.