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.

Gender-specific differences in diabetic neuropathy in BTBR ob/ob mice

“…We identified numerous DEGs with large fold changes in female BTBR ob/ob mice compared to controls (Tables 1 and 2). Among the DEGs identified in DRG tissue, several encode proteins implicated in inflammatory signaling pathways, including Crh (corticotropin releasing hormone), which promotes macrophage foam cell formation (Cho, Kang et al 2015), and Stfa3 (stefin A3), a cysteine protease inhibitor upregulated in lipopolysaccharide-stimulated glial cells (Hosoi, Suzuki et al 2005) that has a role in protecting cells from inappropriate proteolysis. Saa3 (serum amyloid A3) is an acute phase protein that was also highly overexpressed and is association with diabetic complications (Hamano, Saito et al 2004).…”

N-terminal mutation of apoA-I and interaction with ABCA1 reveal mechanisms of nascent HDL biogenesis

“…For each well, 0.8 g of DNA was transfected. Twenty-four hours post transfection, BODIPY-cholesterol (1 M) solubilized in DMSO or mixed with cholesterol (24 g/ml)/methyl--cyclodextrin complex was added to the cells and incubated for 1 h (23)(24)(25)(26)(27). BODIPYcholesterol solubilized in DMSO was used to label cells with basal level cholesterol, while cholesterol/methyl--cyclodextrin/ BODIPY-cholesterol complexes were used to label cells with elevated cholesterol.…”

Effect of Andrographolide on Foam Cell Formation at the Initiation Stage of Atherosclerosis

“…The process of cholesterol efflux involves the ATP-binding cassette (ABC) transporter A1 (ABCA1), ABCG1 and BI-receptor scavenger (SR-BI) [23,24]. Disruption in the process of cholesterol efflux results in cholesterol accumulation in macrophages [25], whereas ABCA1 stimulation can inhibit foam cell formation [26].…”