Role of GPNMB in Foam Cells Formation and Atherosclerosis Progression
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ABSTRACT:
PROVIDER: PRJNA1148641 | ENA |
REPOSITORIES: ENA
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Project description:Currently, both reliable biomarkers for disease monitoring and specific therapeutic targets are needed to combat atherosclerosis, one of the dangerous lipid metabolism disorders. We observed attenuation of atherosclerosis in a GPNMB auto-mutant (GpnmbR150X) mouse model as well as in a myeloid-specific Gpnmb-knockout mouse model. Furthermore, in GpnmbR150X BMDMs, we observed that impaired lipid droplet formation, enhanced lipid oxidative metabolism, and more robust lipid degradation by the lysosomal pathway suppressed the macrophage foaming, thereby reducing the atherosclerotic burden of excess OxLDL.
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Project description:To investigate how GPNMB affected the formation of macrophage-derived foam cells, we performed mass spectrometry on BMDMs from Gpnmb-mutant mouse or control mouse and proteomics analysis of GPNMB-binding proteins in BMDMs.
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Project description:Human genetic studies have repeatedly associated ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury and that the proatherogenicity of ADAMTS7, a secreted protein, is due to its catalytic activity. However, the cell-specific mechanisms governing ADAMTS7 proatherogenicity remain unclear. To determine which vascular cell types express ADAMTS7, we interrogated single-cell RNA sequencing of human carotid atherosclerosis and found ADAMTS7 expression in smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts. We subsequently created SMC- and EC-specific Adamts7 conditional knockout and transgenic mice. Conditional knockout of Adamts7 in either cell type is insufficient to reduce atherosclerosis, whereas transgenic induction in either cell type increases atherosclerosis. In SMC transgenic mice, this increase coincides with an expansion of lipid-laden SMC foam cells and decreased fibrous cap formation. RNA-sequencing in SMCs revealed an upregulation of lipid uptake genes typically assigned to macrophages. Subsequent experiments demonstrated that ADAMTS7 increases SMC oxLDL uptake through increased CD36 levels. Furthermore, Cd36 expression is increased due to increased levels of PU.1, a transcription factor typically associated with myeloid fate determination. In summary, Adamts7 expression in either SMCs or ECs promotes SMC foam cell formation and atherosclerosis. In SMCs, ADAMTS7 promotes oxLDL uptake via increased PU.1 and Cd36 expression, thereby increasing SMC foam cell formation and atherosclerosis.
2026-01-16 | GSE316135 | GEO
Project description:Macrophage-derived foam cell plays a pivotal role in the plaque formation and rupture during the progression of atherosclerosis. Foam cells are destined to divergent cell fate and functions in response to external stimuli based on their internal states, which however is hidden in the traditional studies based on population of cells. Herein, we used time-resolved and single-cell multi-omics to investigate the macrophage heterogeneity along foam cell formation. Dynamic metabolome and lipidome outlined the dual regulating axis of inflammation and ferroptosis. Single cell metabolomics and lipidomics further demonstrated a macrophage continuum featuring a differed susceptibility to apoptosis and ferroptosis. Using single-cell transcriptomic profiling, we verified the divergent cell fate toward apoptosis or ferroptosis. Therefore, the molecular choreography underlying the divergent cell fate during foam cell formation was revealed, which is of high significance for the understanding of the pathogenesis of atherosclerosis and development of new drug targets.
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Project description:<p>Macrophage-derived foam cell plays a pivotal role in the plaque formation and rupture during the progression of atherosclerosis. Foam cells are destined to divergent cell fate and functions in response to external stimuli based on their internal states, which however is hidden in the traditional studies based on population of cells. Herein, we used time-resolved and single-cell multi-omics to investigate the macrophage heterogeneity along foam cell formation. Dynamic metabolome and lipidome outlined the dual regulating axis of inflammation and ferroptosis. Single cell metabolomics and lipidomics further demonstrated a macrophage continuum featuring a differed susceptibility to apoptosis and ferroptosis. Using single-cell transcriptomic profiling, we verified the divergent cell fate toward apoptosis or ferroptosis. Therefore, the molecular choreography underlying the divergent cell fate during foam cell formation was revealed, which is of high significance for the understanding of the pathogenesis of atherosclerosis and development of new drug targets.</p>
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Project description:In atherosclerosis, several immune cells are involved in plaque formation. Foam cell formation is a major cellular process in atherosclerotic lesion. It is important to understand which cells participate in foam cell formation. To characterize the immune cells and foam cells in atherosclerotic aorta, we performed single cell RNA sequencing of aortic CD45+ leukocytes from Ldlr-/- mice and foamy cells from ApoE-/- mice. The single cell RNA-seq analyses revealed the heterogeneity of aortic macrophages and foam cells in atherosclerotic aorta.
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Project description:Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
2025-06-11 | PXD064538 | Pride
Project description:Atherosclerosis arises from disrupted cholesterol metabolism, notably impaired macrophage cholesterol efflux leading to foam cell formation. Through single-cell and bulk RNA sequencing, we identified Listerin as a regulator of macrophage cholesterol metabolism. Listerin expression increased during atherosclerosis progression in humans and rodents. Its deficiency suppressed cholesterol efflux, promoted foam cell formation, and exacerbated plaque features (macrophage infiltration, lipid deposition, necrotic cores) in macrophage-specific knockout mice. Conversely, Listerin overexpression attenuated these atherosclerotic manifestations. Mechanistically, Listerin stabilizes ABCA1, a key cholesterol efflux mediator, by catalyzing K63-linked polyubiquitination at residues K1884/K1957, countering ESCRT-mediated lysosomal degradation of ABCA1 induced by oxLDL. ABCA1 agonist Erythrodiol restored cholesterol efflux in Listerin-deficient macrophages, while ABCA1 knockout abolished Listerin's effects in THP-1 cells. This study establishes Listerin as a protective factor in atherosclerosis via post-translational stabilization of ABCA1, offering a potential therapeutic strategy targeting ABCA1 ubiquitination to enhance cholesterol efflux.
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