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Aims: Redox active ultrafine particles (UFP, d < 0.2 μm) promote vascular oxidative stress and atherosclerosis. Notch signaling is intimately involved in vascular homeostasis, in which forkhead box O1 (FOXO1) acts as a co-activator of the Notch activation complex. We elucidated the importance of FOXO1/Notch transcriptional activation complex to restore vascular regeneration after UFP exposure., Results: In a zebrafish model of tail injury and repair, transgenic Tg(fli1:GFP) embryos developed vascular regeneration at 3 days post amputation (dpa), whereas UFP exposure impaired regeneration (p < 0.05, n = 20 for control, n = 28 for UFP). UFP dose dependently reduced Notch reporter activity and Notch signaling-related genes (Dll4, JAG1, JAG2, Notch1b, Hey2, Hes1; p < 0.05, n = 3). In the transgenic Tg(tp1:GFP; flk1:mCherry) embryos, UFP attenuated endothelial Notch activity at the amputation site (p < 0.05 vs. wild type [WT], n = 20). A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) inhibitor or dominant negative (DN)-Notch1b messenger RNA (mRNA) disrupted the vascular network, whereas notch intracellular cytoplasmic domain (NICD) mRNA restored the vascular network (p < 0.05 vs. WT, n = 20). UFP reduced FOXO1 expression, but not Master-mind like 1 (MAML1) or NICD (p < 0.05, n = 3). Immunoprecipitation and immunofluorescence demonstrated that UFP attenuated FOXO1-mediated NICD pull-down and FOXO1/NICD co-localization, respectively (p < 0.05, n = 3). Although FOXO1 morpholino oligonucleotides (MOs) attenuated Notch activity, FOXO1 mRNA reversed UFP-mediated reduction in Notch activity to restore vascular regeneration and blood flow (p < 0.05 vs. WT, n = 5). Innovation and Conclusion: Our findings indicate the importance of the FOXO1/Notch activation complex to restore vascular regeneration after exposure to the redox active UFP. Antioxid. Redox Signal. 28, 1209-1223.

Ambient particulate matter (PM) exposure is associated with atherosclerosis and inflammatory bowel disease. Ultrafine particles (UFP, d p  < 0.1-0.2 μm) are redox active components of PM. We hypothesized that orally ingested UFP promoted atherogenic lipid metabolites in both the intestine and plasma via altered gut microbiota composition. Low density lipoprotein receptor-null (Ldlr -/- ) mice on a high-fat diet were orally administered with vehicle control or UFP (40 μg/mouse/day) for 3 days a week. After 10 weeks, UFP ingested mice developed macrophage and neutrophil infiltration in the intestinal villi, accompanied by elevated cholesterol but reduced coprostanol levels in the cecum, as well as elevated atherogenic lysophosphatidylcholine (LPC 18:1) and lysophosphatidic acids (LPAs) in the intestine and plasma. At the phylum level, Principle Component Analysis revealed significant segregation of microbiota compositions which was validated by Beta diversity analysis. UFP-exposed mice developed increased abundance in Verrocomicrobia but decreased Actinobacteria, Cyanobacteria, and Firmicutes as well as a reduced diversity in microbiome. Spearman's analysis negatively correlated Actinobacteria with cecal cholesterol, intestinal and plasma LPC18:1, and Firmicutes and Cyanobacteria with plasma LPC 18:1. Thus, ultrafine particles ingestion alters gut microbiota composition, accompanied by increased atherogenic lipid metabolites. These findings implicate the gut-vascular axis in a atherosclerosis model.

Background: Exposure to ambient ultrafine particulate matter (UFP) is a well-recognized risk factor for cardiovascular and respiratory diseases. However, little is known about the effects of air pollution on gastrointestinal disorders., Objective: We sought to assess whether exposure to ambient UFP (diameter < 180 nm) increased free fatty acids and lipid metabolites in the mouse small intestine., Methods: Ldlr-null mice were exposed to filtered air (FA) or UFP collected at an urban Los Angeles, California, site that was heavily affected by vehicular emissions; the exposure was carried out for 10 weeks in the presence or absence of D-4F, an apolipoprotein A-I mimetic peptide with antioxidant and anti-inflammation properties on a high-fat or normal chow diet., Results: Compared with FA, exposure to UFP significantly increased intestinal hydroxyeicosatetraenoic acids (HETEs), including 15-HETE, 12-HETE, 5-HETE, as well as hydroxyoctadecadienoic acids (HODEs), including 13-HODE and 9-HODE. Arachidonic acid (AA) and prostaglandin D2 (PGD2) as well as some of the lysophosphatidic acids (LPA) in the small intestine were also increased in response to UFP exposure. Administration of D-4F significantly reduced UFP-mediated increase in HETEs, HODEs, AA, PGD2, and LPA. Although exposure to UFP further led to shortened villus length accompanied by prominent macrophage and neutrophil infiltration into the intestinal villi, administration of D-4F mitigated macrophage infiltration., Conclusions: Exposure to UFP promotes lipid metabolism, villus shortening, and inflammatory responses in mouse small intestine, whereas administration of D-4F attenuated these effects. Our findings provide a basis to further assess the mechanisms underlying UFP-mediated lipid metabolism in the digestive system with clinical relevance to gut homeostasis and diseases.

Exposure to airborne particulate pollutants is intimately linked to vascular oxidative stress and inflammatory responses with clinical relevance to atherosclerosis. Particulate matter (PM) has been reported to induce endothelial dysfunction and atherosclerosis. Here, we tested whether ambient ultrafine particles (UFP, diameter <200 nm) modulate eNOS activity in terms of nitric oxide (NO) production via protein S-glutathionylation. Treatment of human aortic endothelial cells (HAEC) with UFP significantly reduced NO production. UFP-mediated reduction in NO production was restored in the presence of JNK inhibitor (SP600125), NADPH oxidase inhibitor (Apocynin), anti-oxidant (N-acetyl cysteine), and superoxide dismutase mimetics (Tempol and MnTMPyP). UFP exposure increased the GSSG/GSH ratio and eNOS S-glutathionylation, whereas over-expression of Glutaredoxin-1 (to inhibit S-glutathionylation) restored UFP-mediated reduction in NO production by nearly 80%. Thus, our findings suggest that eNOS S-glutathionylation is a potential mechanism underlying ambient UFP-induced reduction of NO production., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular diseases. The redox-active ultrafine particles (UFPs) promote vascular oxidative stress and inflammatory responses. We hypothesized that UFPs modulated lipid metabolism and anti-oxidant capacity of high density lipoprotein (HDL) with an implication in atherosclerotic lesion size. Fat-fed low density lipoprotein receptor-null (LDLR⁻/⁻ mice were exposed to filtered air (FA) or UFPs for 10 weeks with or without administering an apolipoprotein A-I mimetic peptide made of D-amino acids, D-4F. LDLR⁻/⁻ mice exposed to UFPs developed a reduced plasma HDL level (P < 0.01), paraoxonase activity (P < 0.01), and HDL anti-oxidant capacity (P < 0.05); but increased LDL oxidation, free oxidized fatty acids, triglycerides, serum amyloid A (P < 0.05), and tumor necrosis factor α (P < 0.05), accompanied by a 62% increase in the atherosclerotic lesion ratio of the en face aortic staining and a 220% increase in the cross-sectional lesion area of the aortic sinus (P < 0.001). D-4F administration significantly attenuated these changes. UFP exposure promoted pro-atherogenic lipid metabolism and reduced HDL anti-oxidant capacity in fat-fed LDLR⁻/⁻ mice, associated with a greater atherosclerotic lesion size compared with FA-exposed animals. D-4F attenuated UFP-mediated pro-atherogenic effects, suggesting the role of lipid oxidation underlying UFP-mediated atherosclerosis.

Exposure to atmospheric fine particulate matter (PM(2.5)) is a modifiable risk factor of cardiovascular disease. Ultrafine particles (UFP, diameter <0.1 μm), a subfraction of PM(2.5), promote vascular oxidative stress and inflammatory responses. Epidemiologic studies suggest that PM exposure promotes vascular calcification. Here, we assessed whether UFP exposure promotes vascular calcification via NF-κB signaling. UFP exposure at 50 μg/ml increased alkaline phosphatase (ALP) activity by 4.4 ± 0.2-fold on day 3 (n = 3, P < 0.001) and matrix calcification by 3.5 ± 1.7-fold on day 10 (n = 4, P < 0.05) in calcifying vascular cells (CVC), a subpopulation of vascular smooth muscle cells with osteoblastic potential. Treatment of CVC with conditioned media derived from UFP-treated macrophages (UFP-CM) also led to an increase in ALP activities and matrix calcification. Furthermore, both UFP and UFP-CM significantly increased NF-κB activity, and cotreatment with an NF-κB inhibitor, JSH23, attenuated both UFP- and UFP-CM-induced ALP activity and calcification. When low-density lipoprotein receptor-null mice were exposed to UFP at 359.5 μg/m(3) for 10 wk, NF-κB activation and vascular calcification were detected in the regions of aortic roots compared with control filtered air-exposed mice. These findings suggest that UFP promotes vascular calcification via activating NF-κB signaling.

Exposure to air pollutants increases the incidence of cardiovascular disease. Recent toxicity studies revealed that ultra-fine particles (UFP, d(p)<100-200 nm), the major portion of particulate matter (PM) by numbers in the atmosphere, induced atherosclerosis. In this study, we posited that variations in chemical composition in diesel exhausted particles (DEP) regulated endothelial cell permeability to a different extent. Human aortic endothelial cells (HAEC) were exposed to well-characterized DEP (d(p)<100 nm) emitted from a diesel engine in either idling mode (DEP1) or in urban dynamometer driving schedule (UDDS) (DEP2). Horse Radish Peroxidase-Streptavidin activity assay showed that DEP2 increased endothelial permeability to a greater extent than DEP1 (control=0.077+/-0.005, DEP1=0.175+/-0.003, DEP2=0.265+/-0.006, n=3, p<0.01). DEP2 also down-regulated tight junction protein, Zonular Occludin-1 (ZO-1), to a greater extent compared to DEP1. LDH and caspase-3 activities revealed that DEP-mediated increase in permeability was not due to direct cytotoxicity, and DEP-mediated ZO-1 down-regulation was not due to a decrease in ZO-1 mRNA. Hence, our findings suggest that DEP1 vs. DEP2 differentially influenced the extent of endothelial permeability at the post-translational level. This increase in endothelium permeability is implicated in inflammatory cell transmigration into subendothelial layers with relevance to the initiation of atherosclerosis., ((c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Exposure to particulate air pollution is linked to increased incidences of cardiovascular diseases. Ambient ultrafine particles (UFP) from diesel vehicle engines have been shown to be proatherogenic in ApoE knockout mice and may constitute a major cardiovascular risk in humans. We posited that circulating nano-sized particles from traffic pollution sources induce vascular oxidative stress via JNK activation in endothelial cells. Diesel UFP were collected from a 1998 Kenworth truck. Intracellular superoxide assay revealed that these UFP dose-dependently induced superoxide (O(2)(-)) production in human aortic endothelial cells (HAEC). Flow cytometry showed that UFP increased MitoSOX red intensity specific for mitochondrial superoxide. Protein carbonyl content was increased by UFP as an indication of vascular oxidative stress. UFP also up-regulated heme oxygenase-1 (HO-1) and tissue factor (TF) mRNA expression, and pretreatment with the antioxidant N-acetylcysteine significantly decreased their expression. Furthermore, UFP transiently activated JNK in HAEC. Treatment with the JNK inhibitor SP600125 and silencing of both JNK1 and JNK2 with siRNA inhibited UFP-stimulated O(2)(-) production and mRNA expression of HO-1 and TF. Our findings suggest that JNK activation plays an important role in UFP-induced oxidative stress and stress response gene expression.

Air pollution is a rising public health issue worldwide. Cumulative epidemiological and experimental studies have shown that exposure to air pollution such as particulate matter (PM) is linked with increased hospital admissions and all-cause mortality. While previous studies on air pollution mostly focused on the respiratory and cardiovascular effects, emerging evidence supports a significant impact of air pollution on the gastrointestinal (GI) system. The gut is exposed to PM as most of the inhaled particles are removed from the lungs to the GI tract via mucociliary clearance. Ingestion of contaminated food and water is another common source of GI tract exposure to pollutants. Recent studies have associated air pollution with intestinal diseases, including appendicitis, colorectal cancer, and inflammatory bowel disease. In addition to the liver and adipose tissue, intestine is an important organ system for lipid metabolism, and the intestinal redox lipids might be tightly associated with the intestinal and systematic inflammation. The gut microbiota modulates lipid metabolism and contributes to the initiation and development of intestinal disease including inflammatory bowel disease. Recent data support microbiome implication in air pollution-mediated intestinal and systematic effects. In this review, the associations between air pollution and intestinal diseases, and the alterations of intestinal lipidome and gut microbiome by air pollution are highlighted. The potential mechanistic aspects underlying air pollution-mediated intestinal pathology will also be discussed. Image 1 • Air pollution exposure is associated with the incidence of intestinal disease. • Air pollution promotes the production of pro-inflammatory oxidative lipids. • Air pollution alters the composition/diversity of gut microbiota. • Air pollution-mediated alterations of microbiome might affect lipid metabolism. [ABSTRACT FROM AUTHOR]

Introduction: Ultrafine particles (UFP, d < 0.1 μm), a major sub-fraction of particulate matter (PM2.5, d < 2.5μm) in air pollutant, have been reported to increase cardiovascular morbidity. UFP promote endothelial dysfunction/permeability associated with Notch inhibition and degradation of tight junction protein. Gut vascular barrier (GVB) is a distinct protective barrier that inhibits translocations of antigens across the gut lumen, preventing infections by oral digestions. Here, we hypothesized UFP impair GVB by attenuating Notch signaling and disrupting tight junction protein. Method: The transgenic Tg(flk1:mCherry) zebrafish embryos were immobilized in neutralized tricaine solution and mounted in 2% low melting agarose to perform micro-gavage at 5 days post fertilizations (5dpf). A mA mixture of 10 kD FITC conjugated dextran and phenol red dye wasere micro-gavaged on the intestinal bulb with or without UFP at 25 μg/mL. Anterior trunk and posterior cardinal vein (PCV) post micro-gavage were imaged under a confocal microscope. Notch signaling related genes including the Notch ligand, Dll4, and the target, HES1, and the level of tight junction protein genes zonula occludens-1 (ZO-1) and Occludin (OCLN) mRNA expression following different courses of exposure to UFP were assessed in Human Aortic Endothelial Cells (HAEC) with quantitative RT-PCR., Result: In the control group, the majority of FITC-dextran remained inside the gastrointestinal system. On the other hand, UFP exposure developed a significant accumulation of FITC-dextran in the intersomatic spaces (ISS) between the dorsal aorta (DA) and the PCV. This finding supports evidence of UFP exposure disrupted both the epithelial boundary and the endothelial vascular layer of the gut. In addition, Notch signaling related gene (HES1, DLL4) and the tight junction proteins genes (ZO-1, OCLN) expressions in HAEC were downregulated in concentration and time-course dependent manner by the exposure to UFP. Conclusion: The UFP exposure affected GVB homeostasis and increased endothelial permeability. This finding supports the link between ambient air pollutant exposure to the impairment in the gastrointestinal system. [ABSTRACT FROM AUTHOR]