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Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE150090 | GEO | 2022/03/30

REPOSITORIES: GEO

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Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [bulk RNA-seq]

Project description:Atherosclerotic plaque hypoxia is detrimental for macrophage function. Prolyl hydroxylases (PHDs) initiate cellular responses to hypoxia and may therefore govern macrophage function in plaque hypoxia. PHD inhibitors are clinically investigated to treat anemia in patients with chronic kidney disease, but the consequences for cardiovascular disease are not clear. Hence, we studied the influence of myeloid specific PHD deficiency on atherosclerotic plaque development and stability.

2022-03-30 | GSE150088 | GEO

Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [single-cell RNA-seq]

2022-03-30 | GSE150089 | GEO

Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling

Project description:Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling

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Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [bulk RNA-seq]

Project description:Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [bulk RNA-seq]

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Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [single-cell RNA-seq]

Project description:Deficiency of myeloid PHD proteins aggravates atherogenesis via macrophage apoptosis and paracrine fibrotic signaling [single-cell RNA-seq]

| PRJNA631058 | ENA

Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis.

Project description:Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells in the artery wall. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the progression of atherosclerosis. Here, we define the contribution of miR-21 in hematopoietic cells during atherogenesis. Interestingly, we found that miR-21 is the most abundant miRNA in macrophages and its absence results in accelerated atherosclerosis, plaque necrosis, and vascular inflammation. miR-21 expression influences foam cell formation, sensitivity to ER-stress-induced apoptosis, and phagocytic clearance capacity. Mechanistically, we discovered that the absence of miR-21 in macrophages increases the expression of the miR-21 target gene, MKK3, promoting the induction of p38-CHOP and JNK signaling. Both pathways enhance macrophage apoptosis and promote the post-translational degradation of ABCG1, a transporter that regulates cholesterol efflux in macrophages. Altogether, these findings reveal a major role for hematopoietic miR-21 in atherogenesis.

| S-EPMC5582411 | biostudies-literature

NOX4 regulates macrophage apoptosis resistance to induce fibrotic progression.

Project description:Pulmonary fibrosis is a progressive lung disease often occurring secondary to environmental exposure. Asbestos exposure is an important environmental mediator of lung fibrosis and remains a significant cause of disease despite strict regulations to limit exposure. Lung macrophages play an integral role in the pathogenesis of fibrosis induced by asbestos (asbestosis), in part by generating reactive oxygen species (ROS) and promoting resistance to apoptosis. However, the mechanism by which macrophages acquire apoptosis resistance is not known. Here, we confirm that macrophages isolated from asbestosis subjects are resistant to apoptosis and show they are associated with enhanced mitochondrial content of NADPH oxidase 4 (NOX4), which generates mitochondrial ROS generation. Similar results were seen in chrysotile-exposed WT mice, while macrophages from Nox4-/- mice showed increased apoptosis. NOX4 regulated apoptosis resistance by activating Akt1-mediated Bcl-2-associated death phosphorylation. Demonstrating the importance of NOX4-mediated apoptosis resistance in fibrotic remodeling, mice harboring a conditional deletion of Nox4 in monocyte-derived macrophages exhibited increased apoptosis and were protected from pulmonary fibrosis. Moreover, resolution occurred when Nox4 was deleted in monocyte-derived macrophages in mice with established fibrosis. These observations suggest that NOX4 regulates apoptosis resistance in monocyte-derived macrophages and contributes to the pathogenesis of pulmonary fibrosis. Targeting NOX4-mediated apoptosis resistance in monocyte-derived macrophages may provide a novel therapeutic target to protect against the development and/or progression of pulmonary fibrosis.

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Myeloid Kruppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report.

Project description:To investigate the role of Krüppel-like factor 4 (KLF4), an essential transcriptional regulator of macrophage polarization (M1/M2), in the pathogenesis of atherosclerosis.Despite the acknowledged importance of macrophages in atherosclerosis, the role of M1 (classically activated or proinflammatory) versus M2 (alternatively activated or anti-inflammatory) macrophages in this process remains incompletely understood. We recently identified KLF4 as a regulator of macrophage subset specification; that is, KLF4 promotes M2 and inhibits M1 phenotype. Here, we provide evidence that KLF4-deficient macrophages exhibit enhanced proinflammatory activation and foam cell formation in response to oxidized lipids. In vivo, myeloid KLF4-deficient mice (ApoE(-/-) background) develop significantly more vascular inflammation and atherosclerotic lesion formation.Our findings identify myeloid KLF4 as an essential regulator of vascular inflammation and experimental atherogenesis.

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Myeloid I?B? deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques.

Project description:Activation of the transcription factor NF-?B appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF-?B inhibitor I?B? in atherosclerosis. Myeloid-specific deletion of I?B? results in larger and more advanced lesions in LDL-R-deficient mice without affecting the compositional phenotype of the plaques or systemic inflammatory markers in the plasma. We show that I?B?-deleted macrophages display enhanced adhesion to an in vitro endothelial cell layer, coinciding with an increased expression of the chemokine CCL5. Also, in vivo we found that I?B?(del) mice had more leukocytes adhering to the luminal side of the endothelial cell layers that cover the atherosclerotic plaques. Moreover, we introduce ER-MP58 in this paper as a new immunohistochemical tool for quantifying newly recruited myeloid cells in the atherosclerotic lesion. This staining confirms that in I?B?(del) mice more leukocytes are attracted to the plaques. In conclusion, we show that I?B? deletion in myeloid cells promotes atherogenesis, probably through an induced leukocyte recruitment to plaques.

| S-EPMC3141029 | biostudies-literature

Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance.

Project description:The E3 ubiquitin ligase FBW7 plays critical roles in multiple pathological and physiological processes. Here, we report that after high-fat diet (HFD) feeding for 16 weeks, myeloid-specific FBW7-deficient mice demonstrate increased redox stress, inflammatory responses and insulin resistance. Macrophages activation under FBW7 deficiency decreases substrate flux through the pentose phosphate pathway (PPP) to produce less equivalents (NADPH and GSH) and aggravate the generation of intracellular reactive oxygen species (ROS) in macrophages, thereby over-activating proinflammatory reaction. Mechanistically, we identify that pyruvate kinase muscle isozyme M2 (PKM2) is a new bona fide ubiquitin substrate of SCFFBW7. While challenged with HFD stress, pharmacological inhibition of PKM2 protects FBW7-deficient macrophages against production of ROS, proinflammatory reaction and insulin resistance. Intriguingly, we further find an inverse correlation between FBW7 level and relative higher H2O2 level and the severity of obesity-related diabetes. Overall, the results suggest that FBW7 can play a crucial role in modulating inflammatory response through maintaining the intracellular redox homeostasis during HFD insults.

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