title: Corticotropin-Releasing Hormone (CRH) Promotes Macrophage Foam Cell Formation via Reduced Expression of ATP Binding Cassette Transporter-1 (ABCA1).
abstract: Atherosclerosis, the major pathology of cardiovascular disease, is caused by multiple factors involving psychological stress. Corticotropin-releasing hormone (CRH), which is released by neurosecretory cells in the hypothalamus, peripheral nerve terminals and epithelial cells, regulates various stress-related responses. Our current study aimed to verify the role of CRH in macrophage foam cell formation, the initial critical stage of atherosclerosis. Our quantitative real-time reverse transcriptase PCR (qRT-PCR), semi-quantitative reverse transcriptase PCR, and Western blot results indicate that CRH down-regulates ATP-binding cassette transporter-1 (ABCA1) and liver X receptor (LXR)-α, a transcription factor for ABCA1, in murine peritoneal macrophages and human monocyte-derived macrophages. Oil-red O (ORO) staining and intracellular cholesterol measurement of macrophages treated with or without oxidized LDL (oxLDL) and with or without CRH (10 nM) in the presence of apolipoprotein A1 (apoA1) revealed that CRH treatment promotes macrophage foam cell formation. The boron-dipyrromethene (BODIPY)-conjugated cholesterol efflux assay showed that CRH treatment reduces macrophage cholesterol efflux. Western blot analysis showed that CRH-induced down-regulation of ABCA1 is dependent on phosphorylation of Akt (Ser473) induced by interaction between CRH and CRH receptor 1(CRHR1). We conclude that activation of this pathway by CRH accelerates macrophage foam cell formation and may promote stress-related atherosclerosis.
authors.affiliation: Department of Molecular Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea; Global Top 5 Research Group, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Wonkyoung
authors.initials: W
authors.lastname: Cho
authors.affiliation: Department of Physiology, Tissue Injury Defense Research Center, Ewha Womans University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jihee Lee
authors.initials: JL
authors.lastname: Kang
authors.affiliation: Department of Molecular Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea; Global Top 5 Research Group, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Park
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D003346:Corticotropin-Releasing Hormone; D002784:Cholesterol; D051057:Proto-Oncogene Proteins c-akt