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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 [-]Association of air pollution and greenness with carotid plaque: A prospective cohort study in China
2021
Xie, Yinyu | He, Weiliang | Zhang, Xiaoling | Cui, Jian | Tian, Xiaochao | Chen, Jiang | Zhang, Kaihua | Li, Shanshan | Di, Niu | Xiang, Hao | Wang, Hebo | Chen, Gongbo | Guo, Yuming
Previous studies indicated that exposure to air pollution was associated with the progress of atherosclerosis, but evidence is very limited in China and even in the world. This study aims to assess the associations of long-term exposures to air pollution and greenness with the occurrence of carotid plaque. Participants of this cohort study were urban residents and office workers who visited Hebei General Hospital for routine physical examination annually from September 2016 through to December 2018. Eligible participants were people diagnosed the absence of carotid plaque clinically at their first hospital visit and were followed up at their second or third hospital visit. Exposure to particulate matter with aerodynamic diameter less than 2.5 μm (PM₂.₅), nitrogen dioxide (NO₂) and ozone (O₃) were estimated using an inverse distance weighted (IDW) method. The level of greenness was assessed using the Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI). The associations were evaluated using Cox proportional hazards regression models. Among 4,137 participants, 575 showed the occurrence of carotid plaque during the follow-up period. After controlling for potential confounders, the hazard ratios (HRs) and 95% confidence intervals (95%CIs) of carotid plaque associated with per interquartile range (IQR) increase in PM₂.₅, NO₂, and O₃ were 1.78 (1.55, 2.03), 1.32 (1.14, 1.53) and 1.99 (1.71, 2.31), respectively. Increased EVI and NDVI were significantly associated with lower risk of carotid plaque [HR (and 95%CI): 0.84 (0.77, 0.93) and 0.87 (0.80, 0.94)]. PM₂.₅ significantly mediated 80.47% or 93.00% of the estimated association between EVI or NDVI and carotid plaque. In light of the significant associations between air pollution, greenness and carotid plaque in this study, continued efforts are needed to curb air pollution and plan more green space considering their effects on vascular disease.
Afficher plus [+] Moins [-]Increased risk of carotid atherosclerosis for long-term exposure to indoor coal-burning pollution in rural area, Hebei Province, China
2019
Pang, Yaxian | Zhang, Boyuan | Xing, Dongmei | Shang, Jinmei | Chen, Fengge | Kang, Hui | Chu, Chen | Li, Binghua | Wang, Juan | Zhou, Lixiao | Su, Xuan | Han, Bin | Ning, Jie | Li, Peiyuan | Ma, Shitao | Su, Dong | Zhang, Rong | Niu, Yujie
Smoky coal burning is a predominant manner for heating and cooking in most rural areas, China. Air pollution is associated with the risk of atherosclerosis, however, the link between indoor air pollution induced by smoky coal burning and atherosclerosis is not very clear. Therefore, we designed a cross-sectional study to evaluate the association of long-term exposure to smoky coal burning pollutants with the risk of atherosclerosis. 426 and 326 participants were recruited from Nangong, China and assigned as the coal exposure and control group according to their heating and cooking way, respectively. The indoor air quality (PM2.5, CO, SO₂) was monitored. The association between coal burning exposure and the prevalence of atherosclerosis was evaluated by unconditional logistic regression analysis, adjusted for confounding factors. The inflammatory cytokines mRNAs (IL-8, SAA1, TNF-α, CRP) expression in whole blood were examined by qPCR. People in the coal exposure group had a higher risk of carotid atherosclerosis compared with the control (risk ratio [RR], 1.434; 95% confidence interval [95%CI], 1.063 to 1.934; P = 0.018). The association was stronger in smokers, drinkers and younger (<45 years old) individuals. The elevation of IL-8 (0.24, 95%CI, 0.06–0.58; P < 0.05), CRP (0.37, 95%CI, 0.05–0.70; P < 0.05), TNF-α (0.41, 95%CI, 0.14–0.67; P < 0.01) mRNAs expression in whole blood were positively related to coal exposure. Our results suggested long-term exposure to smoky coal burning emissions could increase the risk of carotid atherosclerosis. The potential mechanism might relate that coal burning emissions exposure induced inflammatory cytokines elevation which had adverse effects on atherosclerotic plaque, and then promoted the development of atherosclerosis.
Afficher plus [+] Moins [-]PM2.5 aggravates the lipid accumulation, mitochondrial damage and apoptosis in macrophage foam cells
2019
Liu, Jiangyan | Liang, Shuang | Du, Zhou | Zhang, Jingyi | Sun, Baiyang | Zhao, Tong | Yang, Xiaozhe | Shi, Yanfeng | Duan, Junchao | Sun, Zhiwei
Epidemiological evidence showed that the particulate matter exposure is associated with atherosclerotic plaque progression, which may be related to foam cell formation, but the mechanism is still unknown. The study was aimed to investigate the toxic effects and possible mechanism of PM2.5 on the formation of macrophage foam cells induced by oxidized low density lipoprotein (ox-LDL). Results showed that PM2.5 induced cytotoxicity by decreasing the cell viability and increasing the LDH level in macrophage foam cells. PM2.5 aggravated the lipid accumulation in ox-LDL-stimulated macrophage RAW264.7 within markedly increasing level of intracellular lipid by Oil red O staining. The level of ROS increased obivously after co-exposure to PM2.5 and ox-LDL than single exposure group. In addition, serious mitochondrial damage such as the mitochondrial swelling, cristae rupturing and disappearance were observed in macrophage foam cells. The loss of the mitochondrial membrane potential (MMP) further exacerbated the mitochondrial damage in PM2.5-induced macrophage foam cells. The apoptotic rate increased more severely via up-regulated protein level of Bax, Cyt C, Caspase-9, Caspase-3, and down-regulated that of Bcl-2, indicating that PM2.5 activated the mitochondrial-mediated apoptosis pathway. In summary, our results demonstrated that PM2.5 aggravated the lipid accumulation, mitochondrial damage and apoptosis in macrophage foam cells, suggesting that PM2.5 was a risk factor of atherosclerosis progression.
Afficher plus [+] Moins [-]Association of polycyclic aromatic hydrocarbons exposure with atherosclerotic cardiovascular disease risk: A role of mean platelet volume or club cell secretory protein
2018
Hu, Chen | Hou, Jian | Zhou, Yun | Sun, Huizhen | Yin, Wenjun | Zhang, Youjian | Wang, Xian | Wang, Guiyang | Chen, Weihong | Yuan, Jing
Inflammation may play an important role in the association between exposure to polycyclic aromatic hydrocarbons (PAHs) and atherosclerotic cardiovascular disease (ASCVD) risk. However, the underlying mechanisms remain unclear.To investigate the association of PAHs exposure with ASCVD risk and effects of mean platelet volume (MPV) or Club cell secretory protein (CC16) on the association.A total of 2022 subjects (689 men and 1333 women) were drawn from the baseline Wuhan residents of the Wuhan-Zhuhai Cohort study. Data on demography and the physical examination were obtained from each participant. Urinary monohydroxy PAH metabolites (OH-PAHs) levels were measured by a gas chromatography-mass spectrometry. We estimated the association between each OH-PAHs and the 10-year ASCVD risk or coronary heart disease (CHD) risk using logistic regression models, and further analyze the mediating effect of MPV or plasma CC16 on the association by using structural equation modeling.The results of multiple logistic regression models showed that some OH-PAHs were positively associated with ASCVD risk but not CHD risk, including 2-hydroxyfluoren (β = 1.761; 95% CI: 1.194–2.597), 9-hydroxyfluoren (β = 1.470; 95% CI: 1.139–1.898), 1-hydroxyphenanthrene (β = 1.480; 95% CI: 1.008–2.175) and ΣOH-PAHs levels (β = 1.699; 95% CI: 1.151–2.507). The analysis of structural equation modeling shows that increased MPV and increased plasma CC16 levels contributed 13.6% and 15.1%, respectively, to the association between PAHs exposure and the 10-year ASCVD risk (p < 0.05).Exposure to PAHs may increase the risk of atherosclerosis, which was partially mediated by MPV or CC16.
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.
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