Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development

Wang, Yidong; Liu, Jia; Xie, Yao; Cai, Zhejun; Liu, Zhenjie; Shen, Jian; Lü, Yi; Wang, Yaping; Su, Sheng-an; Ma, Yuankun; Xiang, Meixiang

doi:10.1016/j.atherosclerosis.2019.08.016

Cited by 58 publications

(42 citation statements)

References 27 publications

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“…To validate that exosome shedding aggravated fatty liver development induced by an AMPKa1 deficiency in vivo, we inhibited exosome secretion with intraperitoneal injections of GW4869 (0.5 mg/kg/day) in HFD-fed Prkaa1 2/2 and Prkaa1 fl/fl :Adipo Cre1 mice for 8 weeks. GW4869 is a ceramide-induced exosome inhibitor (32). Consistent with its known function, GW4869 administration significantly reduced exosome secretion from WAT (Fig.…”

Section: Blocking Exosome Shedding Ablates Hfd-induced Naflsupporting

confidence: 68%

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A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo

Cao

Tian²,

et al. 2020

Diabetes

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Exosomes are important for intercellular communication, but the role of exosomes in the communication between adipose tissue (AT) and the liver remains unknown. The aim of this study is to determine the contribution of AT-derived exosomes in nonalcoholic fatty liver disease (NAFLD). Exosome components, liver fat content, and liver function were monitored in AT in mice fed a high-fat diet (HFD) or treated with metformin or GW4869 and with AMPKα1-floxed (Prkaα1 fl/fl /wild-type [WT]), Prkaα1 −/− , liver tissue-specific Prkaα1 −/− , or AT-specific Prkaα1 −/− modification. In cultured adipocytes and white AT, the absence of AMPKα1 increased exosome release and exosomal proteins by elevating tumor susceptibility gene 101 ( TSG101 )–mediated exosome biogenesis. In adipocytes treated with palmitic acid, TSG101 facilitated scavenger receptor class B (CD36) sorting into exosomes. CD36-containing exosomes were then endocytosed by hepatocytes to induce lipid accumulation and inflammation. Consistently, an HFD induced more severe lipid accumulation and cell death in Prkaα1 −/− and AT-specific Prkaα1 −/− mice than in WT and liver-specific Prkaα1 −/− mice. AMPK activation by metformin reduced adipocyte-mediated exosome release and mitigated fatty liver development in WT and liver-specific Prkaα1 −/− mice. Moreover, administration of the exosome inhibitor GW4869 blocked exosome secretion and alleviated HFD-induced fatty livers in Prkaα1 −/− and adipocyte-specific Prkaα1 −/− mice. We conclude that HFD-mediated AMPKα1 inhibition promotes NAFLD by increasing numbers of AT CD36-containing exosomes.

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Section: Blocking Exosome Shedding Ablates Hfd-induced Naflsupporting

confidence: 68%

“…2F). To determine whether reduced CD63 mediated AMPKa1 deficiencyenhanced exosome secretion, adipocytes were treated with the ceramide-induced exosome inhibitor GW4869 (32). GW4869 enhanced CD63 protein levels (Supplementary Fig.…”

Section: Ampka1 Deficiency Enhances Exosome Release Independently Of Cd63mentioning

confidence: 99%

A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo

Cao

Tian²,

et al. 2020

Diabetes

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“…Based on our observation that Stx2‐Exo induce death of Gb 3 ‐expressing recipient cells (see Figure 3), we hypothesised that blockade of exosome biogenesis and secretion may reduce or prevent exosome‐mediated death of HK‐2 cells. To reduce exosome biogenesis, D‐THP‐1 cells were treated with 20 μM of the neutral sphingomyelinase (nSMase) inhibitor GW4869 prior to intoxication with Stx2; the inhibitor prevents exosome biogenesis (Wang et al, 2019). Treatment of D‐THP‐1 cells with GW4869 alone did not result in cell death, as detected by LDH release assay (data not shown).…”

Section: Resultsmentioning

confidence: 99%

Exosomes released from Shiga toxin 2a–treated human macrophages modulate inflammatory responses and induce cell death in toxin receptor expressing human cells

Lee

et al. 2020

Cellular Microbiology

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Shiga toxins (Stxs) produced by Stx-producing Escherichia coli are the primarily virulence factors of hemolytic uremic syndrome and central nervous system (CNS) impairment. Although the precise mechanisms of toxin dissemination remain unclear, Stxs bind to extracellular vesicles (EVs). Exosomes, a subset of EVs, may play a key role in Stx-mediated renal injury. To test this hypothesis, we isolated exosomes from monocyte-derived macrophages in the presence of Stx2a or Stx2 toxoids. Macrophage-like differentiated THP-1 cells treated with Stxs secreted Stx-associated exosomes (Stx-Exo) of 90-130 nm in diameter, which induced cytotoxicity in recipient cells in a toxin receptor globotriaosylceramide (Gb 3)-dependent manner. Stx2-Exo engulfed by Gb 3-positive cells were translocated to the endoplasmic reticulum in the human proximal tubule epithelial cell line HK-2. Stx2-Exo contained proinflammatory cytokine mRNAs and proteins and induced more severe inflammation than purified Stx2a accompanied by greater death of target cells such as human renal or retinal pigment epithelial cells. Blockade of exosome biogenesis using the pharmacological inhibitor GW4869 reduced Stx2-Exo-mediated human renal cell death. Stx2-Exo isolated from human primary monocyte-derived macrophages activated caspase 3/7 and resulted in significant cell death in primary human renal cortical epithelial cells. Based on these results, we speculate that Stx-containing exosomes derived from macrophages may exacerbate cytotoxicity and inflammation and trigger cell death in toxin-sensitive cells. Therapeutic interventions targeting Stx-containing exosomes may prevent or ameliorate Stx-mediated acute vascular dysfunction. K E Y W O R D S exosome, hemolytic uremic syndrome, human macrophage, human renal epithelial cells, Shiga toxin type 2 1 | INTRODUCTION Shiga toxins (Stxs; also known as verotoxins) secreted by specific strains of Stx-producing Escherichia coli (STEC) and Shigella dysenteriae serotype 1 are major virulence factors that play a role in pathogenesis of hemorrhagic colitis, hemolytic uremic syndrome (HUS), central nervous system (CNS) disorders, blindness and systemic inflammation

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“…The KEGG pathways analysis suggested that DEGs were significantly involved in focal adhesion, PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction, ECM-receptor interaction, amoebiasis, and chemokine signaling pathway. Previous studies showed that the dysfunction of cell adhesion, immune response, inflammatory response, focal adhesion, PI3K-Akt signaling pathway, chemokine signaling pathway, cytokine-cytokine receptor interaction, and ECM-receptor interaction can cause changes in the vascular structure of aneurysms [25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Identification of 2 Potential Core Genes for Influence of Gut Probiotics on Formation of Intracranial Aneurysms by Bioinformatics Analysis

Liu

Yuan

et al. 2020

Med Sci Monit

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Background: Rupture of intracranial aneurysms (IA) is associated with high rates of mortality around the world. Use of intestinal probiotics can regulate the pathophysiology of aneurysms, but the details of the mechanism involved have been unclear. Material/Methods: The GEO2R analysis website was used to detect the DEGs between IAs, AAAs, samples after supplementation with probiotics, and normal samples. The online tool DAVID provides functional classification and annotation analyses of associated genes, including GO and KEGG pathway. PPI of these DEGs was analyzed based on the STRING database, followed by analysis using Cytoscape software. Results: We found 170 intersecting DEGs (contained in GSE75240 and more than 2 of the 4 aneurysms datasets), 5 intersecting DEGs (contained in all datasets) and 1 intersecting DEG (contained in GSE75240 and all IAs datasets). GO analysis results suggested that the DEGs primarily participate in signal transduction, cell adhesion, immune response, response to drug, extracellular matrix organization, cell-cell signaling, and inflammatory response in the BP terms, and the KEGG pathways are mainly enriched in focal adhesion, cytokine-cytokine receptor interaction, ECM-receptor interaction, amoebiasis, chemokine signaling pathway, proteoglycans, and PI3K-Akt signaling pathway in cancer pathways. Through PPI network analysis, we confirmed 2 candidates for further study: CAV1 and MYH11. These downregulated DEGs are associated with the formation of aneurysms, and the change of these DEGs is the opposite in probiotics-treated animals. Conclusions: Our study suggests that MYH11 and CAV1 are potential target genes for prevention of aneurysms. Further experiments are needed to verify these findings.

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Involvement of macrophage-derived exosomes in abdominal aortic aneurysms development

Cited by 58 publications

References 27 publications

A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo

A High-Fat Diet Attenuates AMPK α1 in Adipocytes to Induce Exosome Shedding and Nonalcoholic Fatty Liver Development In Vivo

Exosomes released from Shiga toxin 2a–treated human macrophages modulate inflammatory responses and induce cell death in toxin receptor expressing human cells

Identification of 2 Potential Core Genes for Influence of Gut Probiotics on Formation of Intracranial Aneurysms by Bioinformatics Analysis

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