Monocytes of patients with familial hypercholesterolemia show alterations in cholesterol metabolism

Mosig, Alexander S.; Rennert, Knut; Büttner, Petra; Krause, S.; Lütjohann, Dieter; Soufi, Muhidien; Heller, Regine; Funke, Harald

doi:10.1186/1755-8794-1-60

Cited by 55 publications

(28 citation statements)

References 33 publications

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“…In circulating monocytes from three out of four patients homozygous for familial hypercholesterolemia, the TRPC3 mRNA was notoriously up-regulated compared with heterozygous or control patients (32). Despite these suggestive data showing a correlation between increased expression levels of TRPC3 and presence of atherosclerosis, whether TRPC3 has an active role in the pathogenesis of the human lesion, remains unknown.…”

Section: Discussionmentioning

confidence: 94%

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Smedlund

Birnbaumer

Vázquez

2015

Proc. Natl. Acad. Sci. U.S.A.

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In previous in vitro studies, we showed that Transient Receptor Potential Canonical 3 (TRPC3), a calcium-permeable, nonselective cation channel endowed with high constitutive function, is an obligatory component of the inflammatory signaling that controls expression of the vascular cell adhesion molecule-1 (VCAM-1) and monocyte adhesion to coronary artery endothelial cells. Also, TRPC3 expression in these cells was found to be up-regulated by proatherogenic factors, which enhanced inflammation and VCAM-1 expression. However, it remained to be determined whether these in vitro findings were of relevance to atherosclerotic lesion development in vivo. To answer this important question in the present work, we generated mice with endothelial-specific overexpression of human TRPC3 in an Apoe knockout background (TgEST3ApoeKO) and examined lesions in the aortic sinus following 10 and 16 wk on a high-fat diet. No significant differences were found in size or complexity of early stage lesions (10 wk). However, advanced plaques (16 wk) from TgEST3ApoeKO mice exhibited a significant increase in size and macrophage content compared with nontransgenic littermate controls. Remarkably, this change was correlated with increased VCAM-1 and phospho-IkBα immunoreactivity along the endothelial lining of lesions from transgenic animals compared with controls. These findings validate the in vivo relevance of previous in vitro findings and represent, to our knowledge, the first in vivo evidence for a proatherogenic role of endothelial TRPC3.TRPC3 channels | atherosclerosis | endothelial inflammation

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Section: Discussionmentioning

confidence: 94%

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Smedlund

Birnbaumer

Vázquez

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies have reported that SAA could enhance oxidized LDL-induced foam cell formation, which plays an important role in the pathogenesis of atherosclerosis [37]. Although the epigenetic regulation of this process remains unclear, Jmjd3 expression was increased in patients with familial hypercholesterolemia (FH) compared with healthy individuals [38] (Supplementary Fig. S3A).…”

Section: Resultsmentioning

confidence: 99%

Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages

Yan

Sun

Zhu

et al. 2014

Cellular Signalling

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Serum amyloid A (SAA), a major acute-phase protein, has potent cytokine-like activities in isolated phagocytes and synovial fibroblasts. SAA-induced proinflammatory cytokine gene expression requires transcription factors such as NF-κB; however, the associated epigenetic regulatory mechanism remains unclear. Here we report that Jmjd3, a histone H3 lysine 27 (H3K27) demethylase, is highly inducible in SAA-stimulated macrophages and plays an important role in the induction of inflammatory cytokine genes. SAA-induced Jmjd3 expression leads to reduced H3K27 trimethylation. Silencing of Jmjd3 expression significantly inhibited SAA-induced expression of proinflammatory cytokines including IL-23p19, G-CSF and TREM-1, along with up-regulation of H3K27 trimethylation levels on their promoters. Depletion of Jmjd3 expression also attenuated the release of proinflammatory cytokine genes in a peritonitis model and ameliorated neutrophilia in SAA-stimulated mice. Finally, we observed that Jmjd3 is essential for SAA-enhanced macrophage foam cell formation by oxidized LDL. Taken together, these results illustrate a Jmjd3-dependent epigenetic regulatory mechanism for proinflammatory cytokine gene expression in SAA-stimulate macrophages. This mechanism may be subject to therapeutic intervention for sterile inflammation and atherosclerosis.

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“…Monocytes do express scavenger receptors (SRs) to some degree ( 5-7 ) and are exposed to hypercholesterolemic conditions during disease state. Recent studies in mice and in hypercholesterolemic patients have shown lipid accumulations in blood monocytes (8)(9)(10), but the consequences of cellular lipid accumulation, which have been well characterized in macrophages, are still unclear in monocytes.…”

mentioning

confidence: 99%

Differential lipid metabolism in monocytes and macrophages: influence of cholesterol loading

Fernández-Ruíz

Puchalska

Narasimhulu

et al. 2016

Journal of Lipid Research

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Monocytes of patients with familial hypercholesterolemia show alterations in cholesterol metabolism

Cited by 55 publications

References 33 publications

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Increased size and cellularity of advanced atherosclerotic lesions in mice with endothelial overexpression of the human TRPC3 channel

Jmjd3-mediated epigenetic regulation of inflammatory cytokine gene expression in serum amyloid A-stimulated macrophages

Differential lipid metabolism in monocytes and macrophages: influence of cholesterol loading

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