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.
Highlights
Cardiovascular disease remains the leading cause of death in many developed countries, for which atherosclerosis is the most important underlying pathology [1]
Based on our experiments showing that Corticotropin-releasing hormone (CRH) suppresses cholesterol efflux in macrophages via decreased expression of ATP-binding cassette transporter-1 (ABCA1), we suggest a mechanism by which CRH, the stress hormone, accelerates atherosclerosis and propose the CRH-provoking pathway as a new therapeutic target for the treatment of atherosclerosis
ABCA1, ABCG1 and SR-B1 are known to mediate cholesterol efflux of macrophages, while CD36 and Scavenger receptor-A (SRA) are involved in lipid uptake [15,17]. quantitative real-time reverse transcriptase PCR (qRT-PCR) results using murine peritoneal macrophages revealed that CRH treatment induced 20% decreases in ABCA1 and SR-B1 RNAs
Summary
Cardiovascular disease remains the leading cause of death in many developed countries, for which atherosclerosis is the most important underlying pathology [1]. Corticotropin-Releasing Hormone (CRH) Promotes Foam Cell Formation interplay among many genetic and environmental factors [2]. Psychological factors have been regarded as an important indicator of atherosclerosis [3,4,5]. The mechanism by which psychological stress promotes atherosclerosis is not clearly defined. Corticotropin-releasing hormone (CRH), a 41-amino-acid peptide known to be a stress hormone, links psychological stress to pathophysiologic responses [6]. CRH is released by neurosecretory cells of the paraventricular nucleus in the hypothalamus in response to various physical and psychological stressors, and blood CRH level has been shown to be higher in patients experiencing stress [7,8]. CRH activates resident immune cells in the inflammatory sites and performs pro-inflammatory functions in autocrine and paracrine manners [9,10,11]
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