对氧磷降低RAW264.7巨噬细胞源性泡沫细胞ABCA1表达和胆固醇流出(英文)

Paraoxon Down Regulates ATP-binding Cassette Transporter A1 Expression and Decreases Cholesterol Efflux Through Cyclic AMP Signaling Pathway in RAW 264.7 Macrophage-derived Foam Cells

三磷酸腺苷结合盒转运体A1(ABCA1)是体内胆固醇逆向转运的关键环节.对氧磷是广泛使用的有机磷农药的活性代谢产物.研究发现,对氧磷能增加巨噬细胞中胆固醇的堆积,但具体机制还不清楚.以RAW264.7巨噬细胞源性泡沫细胞为研究对象,观察对氧磷对RAW264.7巨噬细胞源性泡沫细胞ABCA1表达和胆固醇流出的影响并探讨其机制.结果显示,对氧磷以时间和剂量依赖的方式增加RAW264.7巨噬细胞源性泡沫细胞中总胆固醇、游离胆固醇和胆固醇酯水平,降低ABCA1表达和胆固醇流出,同时对氧磷降低细胞中环磷酸腺苷(cAMP)的水平及腺苷酸环化酶(AC)的活性和增加磷酸二酯酶(PDE)的活性,而cAMP的类似物双丁酰环腺苷酸(dBcAMP)能够阻断对氧磷降低ABCA1表达和部分阻断对氧磷降低胆固醇流出,对氧磷导致的cAMP水平的降低也可被AC激动剂福斯高林(Forskolin)和PDE抑制剂3-异丁基-1-甲基黄嘌呤(IBMX)所阻断.以上结果表明,对氧磷通过cAMP信号通路下调RAW264.7巨噬细胞源性泡沫细胞ABCA1的表达,降低细胞内胆固醇流出和增加细胞内胆固醇堆积.

ATP-binding Cassette Transporter A1（ABCA1） plays a critical role in the reverse cholesterol transport（RCT）.Previous studies showed that paraoxon,the active metabolite of organophosphorus insecticide,increased cholesterol retention in macrophages.However,its underlying mechanisms remain to be elucidated.The effect of paraoxon on ABCA1 expression and ABCA1-dependent cholesterol efflux was investigated,and then the role of cyclic adenosine monophospate（cAMP） signaling pathway in the regulation of ABCA1 expression and ABCA1-mediated cholesterol efflux was examined by paraoxon in RAW 264.7 macrophage-derived foam cells.Results showed that paraoxon significantly down regulated ABCA1 expression and reduced ABCA1-dependent cholesterol efflux and increased the levels of the total,free and esterified cholesterols in a time-and dose-dependent manner.Paraoxon also markedly reduced cAMP level and decreased adenylate cyclase（AC） activity and increased cAMP-specific phosphodiesterase（PDE） activity.Furthermore,cAMP analogs dibutyryl cyclic adenosine monophosphate（dBcAMP） markedly compensated the down-regulation of ABCA1 expression and partly compensated the reduction of ABCA1-mediated cholesterol efflux induced by paraoxon.Also,both adenylate cyclase agonist forskolin and phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine（IBMX） markedly compensated the suppression effect on cAMP level induced by paraoxon.In conclusion,the results mentioned above suggest that paraoxon down regulates ABCA1 expression and decreases ABCA1-mediated cholesterol efflux through cyclic AMP signaling pathway in RAW 264.7 macrophage-derived foam cells.