Project description:Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease. MicroRNAs control gene expression at a posttranscriptional level. Altered microRNA expression has been reported in processes related to cardiovascular disease and PM exposure, such as systemic inflammation, endothelial dysfunction, and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM.We investigated the association of exposure to ambient particles in several time windows (4-hour to 28-day moving averages) and blood leukocyte expression changes in 14 candidate microRNAs in 153 elderly males from the Normative Aging Study (examined 2005-2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon, and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathway analysis was performed on target genes of microRNAs associated with the pollutants.We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222, and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two microRNAs; in particular, the "high-mobility group protein B1/advanced glycosylation end product-specific receptor signaling pathway" was shared by miR-126, -146a, -155, -21, and -222. No important associations were observed for miR-125a-5p, -125b, -128, -147, -218, and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925, and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222, and -9, and for rs1640299 in DGCR8 and SO4 for miR-1 and -135a.Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.

Project description:BackgroundAir pollution from particulate matter (PM) has been linked to cardiovascular morbidity and mortality; however the underlying biological mechanisms remain to be uncovered. Gene regulation by microRNAs (miRNAs) that are transferred between cells by extracellular vesicles (EVs) may play an important role in PM-induced cardiovascular risk. This study sought to determine if ambient PM2.5 levels are associated with expression of EV-encapsulated miRNAs (evmiRNAs), and to investigate the participation of such evmiRNAs in pathways related to cardiovascular disease (CVD).MethodsWe estimated the short- (1-day), intermediate- (1-week and 1-month) and long-term (3-month, 6-month, and 1-year) moving averages of ambient PM2.5 levels at participants' addresses using a validated hybrid spatio-temporal land-use regression model. We collected 42 serum samples from 22 randomly selected participants in the Normative Aging Study cohort and screened for 800 miRNAs using the NanoString nCounter® platform. Mixed effects regression models, adjusted for potential confounders were used to assess the association between ambient PM2.5 levels and evmiRNAs. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways that are regulated by PM-associated evmiRNAs.ResultsWe found a significant association between long-term ambient PM2.5 exposures and levels of multiple evmiRNAs circulating in serum. In the 6-month window, ambient PM2.5 exposures were associated with increased levels of miR-126-3p (0.74?±?0.21; p?=?0.02), miR-19b-3p (0.52?±?0.15; p?=?0.02), miR-93-5p (0.78?±?0.22; p?=?0.02), miR-223-3p (0.74?±?0.22; p?=?0.02), and miR-142-3p (0.81?±?0.21; p?=?0.03). Similarly, in the 1-year window, ambient PM2.5 levels were associated with increased levels of miR-23a-3p (0.83?±?0.23; p?=?0.02), miR-150-5p (0.90?±?0.24; p?=?0.02), miR-15a-5p (0.70?±?0.21; p?=?0.02), miR-191-5p (1.20?±?0.35; p?=?0.02), and let-7a-5p (1.42?±?0.39; p?=?0.02). In silico pathway analysis on PM2.5-associated evmiRNAs identified several key CVD-related pathways including oxidative stress, inflammation, and atherosclerosis.ConclusionsWe found an association between long-term ambient PM2.5 levels and increased levels of evmiRNAs circulating in serum. Further observational studies are warranted to confirm and extend these important findings in larger and more diverse populations, and experimental studies are needed to elucidate the exact roles of evmiRNAs in PM-induced CVD.

Project description:BackgroundExposure to particulate matter (PM) is associated with increased incidence of cardiovascular disease and increased coagulation, but the molecular mechanisms underlying these associations remain unknown. Obesity may increase susceptibility to the adverse effects of PM exposure, exacerbating the effects on cardiovascular diseases. Extracellular vesicles (EVs), which travel in body fluids and transfer microRNAs (miRNAs) between tissues, might play an important role in PM-induced cardiovascular risk. We sought to determine whether the levels of PM with an aerodynamic diameter ≤ 10 μm (PM10) are associated with changes in fibrinogen levels, EV release, and the miRNA content of EVs (EV-miRNAs), investigating 1630 overweight/obese subjects from the SPHERE Study.ResultsShort-term exposure to PM10 (Day before blood drawing) was associated with an increased release of EVs quantified by nanoparticle tracking analysis, especially EVs derived from monocyte/macrophage components (CD14+) and platelets (CD61+) which were characterized by flow cytometry. We first profiled miRNAs of 883 subjects by the QuantStudio™ 12 K Flex Real Time PCR System and the top 40 EV-miRNAs were validated through custom miRNA plates. Nine EV-miRNAs (let-7c-5p; miR-106a-5p; miR-143-3p; miR-185-5p; miR-218-5p; miR-331-3p; miR-642-5p; miR-652-3p; miR-99b-5p) were downregulated in response to PM10 exposure and exhibited putative roles in cardiovascular disease, as highlighted by integrated network analysis. PM10 exposure was significantly associated with elevated fibrinogen levels, and five of the nine downregulated EV-miRNAs were mediators between PM10 exposure and fibrinogen levels.ConclusionsResearch on EVs opens a new path to the investigation of the adverse health effects of air pollution exposure. EVs have the potential to act both as markers of PM susceptibility and as potential molecular mechanism in the chain of events connecting PM exposure to increased coagulation, which is frequently linked to exposure and CVD development.

Project description:The role of extracellular vesicles (EVs), specifically exosomes, in intercellular communication likely plays a key role in placental orchestration of pregnancy and maternal immune sensing of the fetus. While murine models are powerful tools to study pregnancy and maternal-fetal immune interactions, in contrast to human placental exosomes, the content of murine placental and pregnancy exosomes remains largely understudied. Using a recently developed in vitro culture technique, murine trophoblast stem cells derived from B6 mice were differentiated into syncytial-like cells. EVs from the conditioned media, as well as from pregnant and non-pregnant sera, were enriched for exosomes. The RNA composition of these murine trophoblast-derived and pregnancy-associated exosome-enriched-EVs (ExoE-EVs) was determined using RNA-sequencing analysis and expression levels confirmed by qRT-PCR. Differentially abundant miRNAs were detected in syncytial differentiated ExoE-EVs, particularly from the X chromosome cluster (mmu-miR-322-3p, mmu-miR-322-5p, mmu-miR-503-5p, mmu-miR-542-3p, and mmu-miR-450a-5p). These were confirmed to be increased in pregnant mouse sera ExoE-EVs by qRT-PCR analysis. Interestingly, fifteen miRNAs were only present within the pregnancy-derived ExoE-EVs compared to non-pregnant controls. Mmu-miR-292-3p and mmu-miR-183-5p were noted to be some of the most abundant miRNAs in syncytial ExoE-EVs and were also present at higher levels in pregnant versus non-pregnant sera ExoE-EVs. The bioinformatics tool, MultiMir, was employed to query publicly available databases of predicted miRNA-target interactions. This analysis reveals that the X-chromosome miRNAs are predicted to target ubiquitin-mediated proteolysis and intracellular signaling pathways. Knowing the cargo of placental and pregnancy-specific ExoE-EVs as well as the predicted biological targets informs studies using murine models to examine not only maternal-fetal immune interactions but also the physiologic consequences of placental-maternal communication.

Dataset Information

Extracellular vesicle-enriched microRNAs interact in the association between long-term particulate matter and blood pressure in elderly men.

Publications

Extracellular vesicle-enriched microRNAs interact in the association between long-term particulate matter and blood pressure in elderly men.

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