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Ractopamine at legal residue dosage accelerates atherosclerosis by inducing endothelial dysfunction and promoting macrophage foam cell formation
2022
Chen, Chia-Hui | Guo, Bei-Chia | Hu, Po-An | Lee, Hsueh-Te | Hu, Hsuan-Yun | Hsu, Man-Chen | Chen, Wen-Hua | Lee, Tzong-Shyuan
Ractopamine, a synthetic β-adrenoreceptor agonist, is used as an animal feed additive to increase food conversion efficiency and accelerate lean mass accretion in farmed animals. The U.S. Food and Drug Administration claimed that ingesting products containing ractopamine residues at legal dosages might not cause short-term harm to human health. However, the effect of ractopamine on chronic inflammatory diseases and atherosclerosis is unclear. Therefore, we investigated the effects of ractopamine on atherosclerosis and its action mechanism in apolipoprotein E-null (apoe⁻/⁻) mice and human endothelial cells (ECs) and macrophages. Daily treatment with ractopamine for four weeks increased the body weight and the weight of brown adipose tissues and gastrocnemius muscles. However, it decreased the weight of white adipose tissues in apoe⁻/⁻ mice. Additionally, ractopamine exacerbated hyperlipidemia and systemic inflammation, deregulated aortic cholesterol metabolism and inflammation, and accelerated atherosclerosis. In ECs, ractopamine treatment induced endothelial dysfunction and increased monocyte adhesion and transmigration across ECs. In macrophages, ractopamine dysregulated cholesterol metabolism by increasing oxidized low-density lipoprotein (oxLDL) internalization and decreasing reverse cholesterol transporters, increasing oxLDL-induced lipid accumulation. Collectively, our findings revealed that ractopamine induces EC dysfunction and deregulated cholesterol metabolism of macrophages, which ultimately accelerates atherosclerosis progression.
Afficher plus [+] Moins [-]Polychlorinated biphenyl quinone promotes macrophage polarization to CD163+ cells through Nrf2 signaling pathway
2020
Liu, Jing | Yang, Bingwei | Wang, Yuting | Wu, Yunjie | Fan, Bailing | Zhu, Sixi | Song, Erqun | Song, Yang
Polychlorinated biphenyls (PCBs) are notorious environmental pollutants. For their hydrophobic and lipophilic capability, they are wildly spread to environment to threat human health thus attracts more attention. In this study, we observed increasing numbers of CD163 positive (CD163⁺) macrophages in aortic valve of ApoE⁻/⁻ mice after 2,3,5-trichloro-6-phenyl-[1,4]-benzoquinone (PCB29-pQ) treatment, the metabolite of polychlorinated biphenyl. In addition, in vitro studies identified that PCB29-pQ exposure significantly provoked the shifting of RAW264.7 macrophages and bone marrow derived monocytes (BMDMs) to CD163⁺ macrophages. Upon PCB29-pQ administration, CD163 and CD206 levels were enhanced in RAW264.7 cells as well as in BMDMs. However, the concentration of iron and total cholesterol (TC) were reduced due to the boosting of ferroportin (Fpn) and ATP binding cassette transporter, subfamily A, member 1 (ABCA1) which are efflux transporters of iron and cholesterol individually. Further investigation on mechanism indicated that PCB29-pQ exposure induced reactive oxygen species (ROS), which may result in activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a protein responsible for macrophage polarization. After that, we blocked Nrf2 through Nrf2 shRNA and ROS scavenger NAC, which significantly reversed the shifting of macrophage to CD163⁺ sub-population. These results confirmed the importance of Nrf2 in inducing macrophage polarization. In short, our study uncovered that PCB29-pQ could promote macrophage/monocyte polarization to CD163⁺ macrophage which would be a potential incentive to accelerate atherosclerosis through Nrf2 signaling pathway.
Afficher plus [+] Moins [-]Phthalate exposure increases subclinical atherosclerosis in young population
2019
Su, Ta-Chen | Hwang, Jing-Shiang | Torng, Pao-Ling | Wu, Charlene | Lin, Chien-Yu | Sung, Fung-Chang
The link between phthalate exposure and the risk of subclinical atherosclerosis in young population remains unclear. This study investigated the association between phthalate exposure and subclinical atherosclerosis, in terms of carotid intima-media thickness (CIMT), in young population. From a nationwide mass urine screening for renal health, conducted in 1992–2000 among school children 6–18 years of age in Taiwan, we recruited 789 subjects to participate in the cardiovascular health examination in 2006–2008. Among them, 787 received measurements of 7 urinary phthalate metabolites and CIMT. Results showed both mean and maximal values of CIMT at all segments of carotid arteries significantly increased with the urinary mono-2-ethylhexyl phthalate (MEHP), ∑ di-(2-ethylhexyl) phthalate (DEHP), and mono-n-butyl phthalate (MnBP) in a dose-response relationship after adjustment for multiple linear regression models. Multivariate logistic regression analysis showed that higher quartiles of urinary concentrations of MEHP, ∑DEHP, and MnBP were associated with a higher risk of thicker CIMT. Compared to subjects with the lowest quartile (Q1) of urinary MEHP, the adjusted odds ratios (95% confidence interval) for thicker CIMT among subjects with higher urinary MEHP were 2.13 (1.18–3.84) at Q2, 4.02 (2.26–7.15) at Q3 and 7.39 (4.16–13.12) at the highest Q4. In conclusion, urinary phthalate metabolites of MEHP, ∑DEHP, and MnBP are strongly associated with CIMT in adolescents and young adults in Taiwan.
Afficher plus [+] Moins [-]Elevated inflammatory Lp-PLA2 and IL-6 link e-waste Pb toxicity to cardiovascular risk factors in preschool children
2018
Lu, Xueling | Xu, Xijin | Zhang, Yu | Zhang, Yuling | Wang, Chenyang | Huo, Xia
Cardiovascular toxicity of lead (Pb) manifests primarily as an effect on blood pressure and eventual increased risk of atherosclerosis and cardiovascular events. Therefore, we investigated vascular inflammatory biomarkers and cardiovascular effects of Pb-exposed children. A total of 590 children (3–7 years old) were recruited from Guiyu (n = 337), an electronic waste (e-waste)-exposed group, and Haojiang (n = 253), a reference group, from November to December 2016. We measured child blood Pb levels (BPbs), and systolic and diastolic blood pressure. Pulse pressure was calculated for the latter two. Serum biomarkers including lipid profiles and inflammatory cytokines, and plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) were detected. Unadjusted regression analysis illustrated that higher ln-transformed BPb associated with lower systolic blood pressure and pulse pressure. After adjustment for various confounders, the relational degree of lnBPb and blood pressure measures became slightly attenuated or not significant. Elevated BPb was associated with higher Lp-PLA2, interleukin (IL)-6, triglycerides (TG) and lower high-density lipoprotein (HDL). Lp-PLA2 remained inversely associated with pulse pressure and HDL, but positively with ratios of total cholesterol to HDL (Tc/HDL) and low-density lipoprotein to HDL (LDL/HDL). IL-6 was associated negatively with systolic blood pressure, pulse pressure and HDL, and positively associated with TG, Tc/HDL and LDL/HDL. The mediation effect of biomarkers on the association of BPb with pulse pressure was insignificant except for Lp-PLA2. Available data supports the conclusion that e-waste-exposed children with higher BPbs and concomitant abnormal measures of cardiovascular physiology have an augmented prevalence of vascular inflammation, as well as lipid disorder.
Afficher plus [+] Moins [-]Dioxin-like PCB 126 increases intestinal inflammation and disrupts gut microbiota and metabolic homeostasis
2018
Petriello, Michael C. | Hoffman, Jessie B. | Vsevolozhskaya, Olga | Morris, Andrew J. | Hennig, Bernhard
The gut microbiome is sensitive to diet and environmental exposures and is involved in the regulation of host metabolism. Additionally, gut inflammation is an independent risk factor for the development of metabolic diseases, specifically atherosclerosis and diabetes. Exposures to dioxin-like pollutants occur primarily via ingestion of contaminated foods and are linked to increased risk of developing cardiometabolic diseases. We aimed to elucidate the detrimental impacts of dioxin-like pollutant exposure on gut microbiota and host gut health and metabolism in a mouse model of cardiometabolic disease. We utilized 16S rRNA sequencing, metabolomics, and regression modeling to examine the impact of PCB 126 on the microbiome and host metabolism and gut health. 16S rRNA sequencing showed that gut microbiota populations shifted at the phylum and genus levels in ways that mimic observations seen in chronic inflammatory diseases. PCB 126 reduced cecum alpha diversity (0.60 fold change; p = 0.001) and significantly increased the Firmicutes to Bacteroidetes ratio (1.63 fold change; p = 0.044). Toxicant exposed mice exhibited quantifiable concentrations of PCB 126 in the colon, upregulation of Cyp1a1 gene expression, and increased markers of intestinal inflammation. Also, a significant correlation between circulating Glucagon-like peptide-1 (GLP-1) and Bifidobacterium was evident and dependent on toxicant exposure. PCB 126 exposure disrupted the gut microbiota and host metabolism and increased intestinal and systemic inflammation. These data imply that the deleterious effects of dioxin-like pollutants may be initiated in the gut, and the modulation of gut microbiota may be a sensitive marker of pollutant exposures.
Afficher plus [+] Moins [-]Associations of exposure to residential green space and neighborhood walkability with coronary atherosclerosis in Chinese adults
2022
Hu, Hai-Bo | Hou, Zhi-Hui | Huang, Cong-Hong | LaMonte, Michael J. | Wang, Meng | Lü, Bin
Residential green space and neighborhood walkability are important foundations of a healthy and sustainable city. Yet, their associations with atherosclerosis, the disease underlying clinical coronary heart disease (CHD), is unknown, especially in susceptible populations. We aim to explore the associations of exposure to residential green space and neighborhood walkability with coronary atherosclerosis. In this study of 2021 adults with suspected CHD, we evaluated the associations of exposure to green space (using Normalized Difference Vegetation Index [NDVI] and enhanced vegetation index [EVI] surrounding each participant's home) and neighborhood walkability (using walkability index and number of parks near home) with atherosclerosis (using coronary artery calcium score, CAC) using linear regression model adjusted for individual-level characteristics. Mediation analysis was further applied to explore potential mechanisms through the pathways of physical activity, air pollution, and psychological stress. In the primary model, an interquartile increase in annual mean NDVI and EVI within the 1-km area was associated with −15.8% (95%CI: 28.7%, −0.7%), and −18.6% (95%Cl: 31.3%, −3.6%) lower CAC score, respectively. However, an interquartile increase in the walkability index near home was associated with a 7.4% (95% CI: 0.1%, 15.2%) higher CAC score. The combined exposure to a green space area in a 1-km area and the walkability index were inversely associated with atherosclerosis, albeit with a smaller magnitude than a single-exposure model. The findings from a mediation analysis suggested that increased physical exercise and ameliorated particulate matter <2.5 μm (PM₂.₅) may partially contribute to the relationship between green space and atherosclerosis, and for walkability index, partially explained by increased PM₂.₅ exposure. Our study suggested a beneficial association between green space and atherosclerosis, but an adverse association between neighborhood walkability and atherosclerosis. Therefore, urban development that aims to improve neighborhood walkability should jointly account for enhancing green space properties from a public health perspective.
Afficher plus [+] Moins [-]Short-term exposure to air pollution and biomarkers of cardiovascular effect: A repeated measures study
2021
Ni, Yu | Tracy, Russell P. | Cornell, Elaine | Kaufman, Joel D. | Szpiro, Adam A. | Campen, Matthew J. | Vedal, Sverre
To help understand the pathophysiologic mechanisms linking air pollutants and cardiovascular disease (CVD), we employed a repeated measures design to investigate the associations of four short-term air pollution exposures – particulate matter less than 2.5 μm in diameter (PM₂.₅), nitrogen dioxide (NO₂), ozone (O₃) and sulfur dioxide (SO₂), with two blood markers involved in vascular effects of oxidative stress, soluble lectin-like oxidized LDL receptor-1 (sLOX-1) and nitrite, using data from the Multi-Ethnic Study of Atherosclerosis (MESA). Seven hundred and forty participants with plasma sLOX-1 and nitrite measurements at three exams between 2002 and 2007 were included. Daily PM₂.₅, NO₂, O₃ and SO₂ zero to seven days prior to blood draw were estimated from central monitors in six MESA regions, pre-adjusted using site-specific splines of meteorology and temporal trends, and an indicator for day of the week. Unconstrained distributed lag generalized estimating equations were used to estimate net effects over eight days with adjustment for sociodemographic and behavioral factors. The results showed that higher short-term concentrations of PM₂.₅, but not other pollutants, were associated with increased sLOX-1 analyzed both as a continuous outcome (percent change per interquartile increase: 16.36%, 95%CI: 0.1–35.26%) and dichotomized at the median (odds ratio per interquartile increase: 1.21, 95%CI: 1.01–1.44). The findings were not meaningfully changed after adjustment for additional covariates or in several sensitivity analyses. Pollutant concentrations were not associated with nitrite levels. This study extends earlier experimental findings of increased sLOX-1 levels following PM inhalation to a much larger population and at ambient concentrations. In light of its known mechanistic role in promoting vascular disease, sLOX-1 may be a suitable translational biomarker linking air pollutant exposures and cardiovascular outcomes.
Afficher plus [+] Moins [-]Relationship between life-time exposure to ambient fine particulate matter and carotid artery intima-media thickness in Australian children aged 11–12 years
2021
Guo, Yue Leon | Ampon, Rosario D. | Hanigan, Ivan C. | Knibbs, Luke D. | Geromboux, Christy | Su, Ta-Chen | Negishi, Kazuaki | Poulos, Leanne | Morgan, Geoffrey G. | Marks, Guy B. | Jalaludin, Bin
Long-term exposure to air pollutants, especially particulates, in adulthood is related to cardiovascular diseases and vascular markers of atherosclerosis. However, whether vascular changes in children is related to exposure to air pollutants remains unknown. This study examined whether childhood exposure to air pollutants was related to a marker of cardiovascular risk, carotid intima–media thickness (CIMT) in children aged 11–12 years old. Longitudinal Study of Australian Children (LSAC) recruited parents and their children born in 2003–4. Among the participants, CheckPoint examination was conducted when the children were 11–12 years old. Ultrasound of the right carotid artery was performed using standardized protocols. Average and maximum far-wall CIMT, carotid artery distensibility, and elasticity were quantified using semiautomated software. Annual and life-time exposure to air pollutants was estimated using satellite-based land-use regression by residential postcodes. A total of 1063 children (50.4% girls) with CIMT data, serum cholesterol, and modeled estimates of NO₂ and PM₂.₅ exposure for the period 2003 to 2015 were included. The average and maximum CIMT, carotid distensibility, and elasticity were 497 μm (standard deviation, SD 58), 580 μm (SD 44), 17.4% (SD 3.2), and 0.48%/mmHg (SD 0.09), respectively. The life-time average concentrations of PM₂.₅ and NO₂ were 6.4 μg/m³ (SD 1.4) and 6.4 ppb (SD 2.4), respectively. Both average and maximum CIMT were significantly associated with average ambient PM₂.₅ concentration (average CIMT: +5.5 μm per μg/m³, 95% confidence interval, CI 2.4 to 8.5, and maximum CIMT: +4.9 μm per μg/m³, CI 2.3 to 7.6), estimated using linear regression, adjusting for potential confounders. CIMT was not significantly related to NO₂ exposure. Carotid artery diameter, distensibility, and elasticity were not significantly associated with air pollutants. We conclude that life-time exposure to low levels of PM₂.₅ in children might have measurable adverse impacts on vascular structure by age 11–12 years.
Afficher plus [+] Moins [-]The association between urine di-(2-ethylhexyl) phthalate metabolites, global DNA methylation, and subclinical atherosclerosis in a young Taiwanese population
2020
Lin, Chien-Yu | Lee, Hui-Ling | Hwang, Yi-Ting | Wang, Chikang | Hsieh, Chia-Jung | Wu, Charlene | Sung, Fung-Chang | Su, Ta-Chen
Di-(2-ethylhexyl) phthalate (DEHP) has been utilized in many products for years. DEHP exposure has been linked to cardiovascular diseases (CVD) and its risk factors. Recent evidence has found a crucial role for epigenetics, including DNA methylation, in CVD. Moreover, DEHP exposure has proved to alter DNA methylation in epidemiological studies. However, the interplay between DEHP exposure, global DNA methylation, and atherosclerosis has never been reported. In this current study, we enrolled 793 participants (12–30 years) from a Taiwanese population to investigate the association between concentrations of DEHP metabolites, 5mdC/dG (global DNA methylation marker) and the carotid intima-media thickness (CIMT). The results showed urine mono-2-ethylhexyl phthalate (MEHP) level was positively correlated with 5mdC/dG and CIMT, respectively. In logistic regression models, the odds ratios (OR) of thicker CIMT (greater than 75ᵗʰ percentile) with one unit increase in ln-MEHP level was higher when levels of 5mdC/dG were above 50%. In structural equation model, the result showed urine MEHP levels are directly associated with CIMT. Moreover, MEHP had an indirect association with CIMT through the 5mdC/dG after adjusting other confounding effects. In the current study, urine DEHP metabolite levels were positively correlated with 5mdC/dG, and CIMT. Our results showed DEHP had a direct and indirect association with CIMT through the 5mdC/dG. The finding implies that DNA methylation may mediate the association between DEHP exposures and subclinical atherosclerosis in this young population. Future effort is needed to elucidate the causal relationship between DEHP exposure, DNA methylation and CVD.
Afficher plus [+] Moins [-]Acrolein-induced apoptosis of smooth muscle cells through NEAT1-Bmal1/Clock pathway and a protection from asparagus extract
2020
Chen, Lijun | Wu, Xiaoyue | Zeb, Falak | Huang, Yunxiang | An, Jing | Jiang, Pan | Chen, Aochang | Xu, Chuyue | Feng, Qing
Apoptosis of vascular smooth muscle cells (VSMCs) accelerates manifestation of plaque vulnerability in atherosclerosis. Long noncoding RNA NEAT1 participates in the proliferation and apoptosis of cells. In addition, circadian clock genes play a significant role in cell apoptosis. However, whether acrolein, an environmental pollutant, affects the apoptosis of VSMCs by regulating NEAT1 and clock genes is still elusive. We established VSMCs as an atherosclerotic cell model in vitro. Acrolein exposure reduced survival rate of VSMCs, and raised apoptosis percentage through upregulating the expression of Bax, Cytochrome c and Cleaved caspase-3 and downregulating Bcl-2. Asparagus extract (AE), as a dietary supplementation, was able to protect VSMCs against acrolein-induced apoptosis. Expression of NEAT1, Bmal1 and Clock was decreased by acrolein, while was ameliorated by AE. Knockdown of NEAT1, Bmal1 or Clock promoted VSMCs apoptosis by regulating Bax, Bcl-2, Cytochrome c and Caspase-3 levels. Correspondingly, overexpression of NEAT1 inhibited the apoptosis. We also observed that silence of NEAT1 repressed the expression of Bmal1/Clock and vice versa. In this study, we demonstrated that VSMCs apoptosis induced by acrolein was associated with downregulation of NEAT1 and Bmal1/Clock. AE alleviated the effects of proapoptotic response and circadian disorders caused by acrolein, which shed a new light on cardiovascular protection.
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