Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II.
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.
Takata
Yasunori
Y
Division of Endocrinology, Diabetes, and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Chu
Van
V
Collins
Alan R
AR
Lyon
Christopher J
CJ
Wang
Wei
W
Blaschke
Florian
F
Bruemmer
Dennis
D
Caglayan
Evren
E
Daley
William
W
Higaki
Jitsuo
J
Fishbein
Michael C
MC
Tangirala
Rajendra K
RK
Law
Ronald E
RE
Hsueh
Willa A
WA
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced*; D002784:Cholesterol / Q000378:metabolism; D051921:Fos-Related Antigen-2 / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000502:physiology; D012097:Repressor Proteins / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D000097382:CD68 Molecule
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000804:Angiotensin II; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D002784:Cholesterol; D051921:Fos-Related Antigen-2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D012097:Repressor Proteins; C577836:ABCA1 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule