Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II.
Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II.
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巨噬细胞中 ATP 结合盒转运蛋白 A1 基因的转录抑制：血管紧张素 II 的新型动脉粥样硬化作用。
DOI：
10.1161/01.res.0000190400.46267.7e
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Hsueh,WillaA
中科院分区：
文献类型：
--
作者：
Takata,Yasunori;Chu,Van;Collins,AlanR;Lyon,ChristopherJ;Wang,Wei;Blaschke,Florian;Bruemmer,Dennis;Caglayan,Evren;Daley,William;Higaki,Jitsuo;Fishbein,MichaelC;Tangirala,RajendraK;Law,RonaldE;Hsueh,WillaA
Angiotensin II (Ang II) is a powerful accelerator of atherosclerosis. Herein, we describe a novel transcription mechanism through which Ang II inhibits macrophage expression of the ATP-binding cassette transporter A1 (ABCA1), a key regulator of reverse cholesterol transport. We demonstrate that chronic Ang II infusion substantially promotes macrophage infiltration, foam cell formation, and atherosclerosis in low-density lipoprotein receptor-deficient mice and significantly reduces ABCA1 expression in peripheral macrophages. Administration of the Ang II type 1 receptor blocker valsartan inhibited Ang II-induced ABCA1 mRNA repression, macrophage cholesterol accumulation, and atherosclerosis. Ang II treatment reduced ABCA1 promoter activity of in vitro cultured mouse peritoneal macrophages, inducing fos-related antigen 2 (Fra2) protein binding to an ABCA1 promoter E-box motif, a site known to negatively regulate macrophage ABCA1 transcription. Valsartan pretreatment blocked Fra2 binding to the ABCA1 promoter, and Fra2 small interfering RNA pretreatment attenuated Ang II-mediated ABCA1 transcriptional inhibition, confirming the role of Fra2 in this process. This new evidence suggests that Ang II, a well-known proinflammatory and pro-oxidative factor, alters macrophage cholesterol homeostasis by repressing ABCA1 to promote foam cell formation and atherosclerosis.
