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Evaluation of fine particulate matter on vascular endothelial function in vivo and in vitro
Abstract
Ambient fine particulate matter (PM2.5) and high-fat diet (HFD) are linked to the development of atherosclerosis. However, there is still unknown about the PM2.5-induced atherosclerosis formation on vascular endothelial injury after co-exposed to PM2.5 and HFD. Thus, the aim of this study was to evaluate the effects of PM2.5 on atherogenesis in C57BL/6 mice and endothelial cells, as well as the co-exposure effect of PM2.5 and HFD. In vivo study, C57BL/6 mice exposed to PM2.5 and fed with standard chow diet (STD) or HFD for 1 month. PM2.5 could increase vascular stiffness accessed by Doppler ultrasound, and more serious in co-exposure group. PM2.5 impaired vascular endothelial layer integrity, exfoliated endothelial cells, and inflammatory cells infiltration through H&E staining. PM2.5 reduced the expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) in vessel. Moreover, PM2.5 could induce systemic inflammation detected by Mouse Inflammation Array. In vitro study, PM2.5 triggered markedly mitochondrial damage by transmission electron microscope (TEM) and flow cytometer. Inflammatory cytokines were significantly increased in PM2.5-exposed group. The cell viability and migration of endothelial cells were significantly suppressed. In addition, PM2.5 remarkably declined the expression of vascular endothelial growth factor receptor 2 (VEGFR2) and increased the expression of somatostatin (SST) and its receptor. In conclusion, co-exposure of PM2.5 and HFD might induce systemic inflammation and endothelial dysfunction in normal mice. Moreover, PM2.5 could reduce vascular endothelial repair capacity through inhibiting the proliferation and migration of endothelial cells.
... The main, but not the only mechanisms for the development and progression of atherosclerosis are oxidative stress, inflammation, endothelial dysfunction, lipid metabolism disorders, hemostasis disorders and impaired functioning of the autonomic nervous system (ANS). Since the formation of atherosclerotic plaques is an extremely complex and multistage process, involving the interaction of a number of cell populations (endothelial cells, monocytes, macrophages, smooth muscle cells, T-lymphocytes, etc.) and mechanisms [58][59][60], for a more holistic and accurate understanding of the role played by PM 2.5 in the development of atherosclerosis, one should consider separately the specific effect of PM 2.5 on each of the above-mentioned components and mechanisms. Therefore, below we will sequentially consider the effect of PM 2.5 on the above-mentioned mechanisms underlying the proatherogenic effect of PM 2.5. ...
... Endothelial dysfunction is one of the generally recognized initiating mechanisms underlying the development and progression of atherosclerosis [58]. Under normal conditions, vascular endothelial cells produce a number of regulatory biologically active compounds that cause narrowing and dilation of blood vessels, depending on the existing needs of the human body. ...
... As a result of endotheliocyte damage, the barrier function of the endothelium weakens, which leads to increased transportation of many components of blood plasma, including LDLs through the endothelial barrier into the subendothelial space, where these atherogenic particles are accumulated/oxidized, subsequently initiating the formation of an arterial sclerotic disease [60][61][62]. LDL particles accumulated in the vascular walls undergo oxidation by RNS produced by endothelial cells and macrophages, which leads to the formation of ox-LDLs, the accumulation of which impairs the function of endothelial cells, completing the vicious pathogenetic circle [58,62]. ...
Due to the fact that atherosclerotic cardiovascular diseases (CVDs) dominate in the structure of morbidity, disability and mortality of the population, the study of the risk factors for the development of atherosclerotic CVDs, as well as the study of the underlying pathogenetic mechanisms thereof, is the most important area of scientific research in modern medicine. Understanding these aspects will allow to improve the set of treatment and preventive measures and activities. One of the important risk factors for the development of atherosclerosis, which has been actively studied recently, is air pollution with fine particulate matter (PM 2.5). According to clinical and epidemiological data, the level of air pollution with PM 2.5 exceeds the normative indicators in most regions of the world and is associated with subclinical markers of atherosclerosis and mortality from atherosclerotic CVDs. The aim of this article is to systematize and discuss in detail the role of PM 2.5 in the development of atherosclerosis and myocardial damage.
... The main but not the only mechanisms for the development and progression of atherosclerosis are oxidative stress, inflammation, endothelial dysfunction, lipid metabolism disorders, hemostasis disorders and impaired functioning of the vegetative nervous system. Since the formation of ather-osclerotic plaques is an extremely complex and multistage process involving the interaction of a number of cell populations (endothelial cells, monocytes, macrophages, smooth muscle cells, T-lymphocytes, etc.) and mechanisms [51][52][53], for a more holistic and accurate understanding of the role, played by PM 2.5 in the development of atherosclerosis, one should consider separately the specific effect of PM 2.5 on each of the above-mentioned components and mechanisms. Therefore, in the next sections, we will sequentially consider the effect of PM 2.5 on the above-mentioned mechanisms underlying the proatherogenic effect of PM 2.5. ...
... Endothelial dysfunction is one of the generally recognized initiating mechanisms underlying the development and progression of atherosclerosis [51]. Under normal conditions, vascular endothelial cells produce a number of regulatory biologically active compounds that cause narrowing and dilation of blood vessels, depending on the existing needs of the human body. ...
... As a result of endotheliocyte damage, the barrier function of the endothelium weakens, which leads to increased transportation of many components of blood plasma, including LDLs, through the endothelial barrier into the subendothelial space, where these atherogenic particles are accumulated/oxidized, subsequently initiating the formation of an arterial sclerotic disease [53][54][55]. LDL particles accumulated in the vascular walls undergo oxidation by RNS produced by endothelial cells and macrophages, which leads to the formation of ox-LDLs, the accumulation of which impairs the function of endothelial cells, completing the vicious pathogenetic circle [51,55]. ...
Due to the fact that atherosclerotic cardiovascular diseases (CVDs) dominate in the structure of morbidity, disability and mortality of the population, the study of the risk factors for the development of atherosclerotic CVDs, as well as the study of the underlying pathogenetic mechanisms thereof, is the most important area of scientific research in modern medicine. Understanding these aspects will allow to improve the set of treatment and preventive measures and activities. One of the important risk factors for the development of atherosclerosis, which has been actively studied recently, is air pollution with fine particulate matter (PM 2.5). According to clinical and epidemiological data, the level of air pollution with PM 2.5 exceeds the normative indicators in most regions of the world and is associated with subclinical markers of atherosclerosis and mortality from atherosclerotic CVDs.
The aim
of this article is to systematize and discuss in detail the role of PM 2.5 in the development of atherosclerosis and myocardial damage with consideration of epidemiological and pathogenetic aspects
Materials and method
This narrative review is based on the analysis of publications in the Medline, PubMed, and Embase databases. The terms "fine particles" and "PM 2.5" in combination with "pathophysiological mechanisms," "cardiovascular diseases", "atherosclerosis", "cardiac troponins", "myocardial damage" and "myocardial injury" were used to search publications.
Conclusion
. According to the conducted narrative review, PM 2.5 should be regarded as the significant risk factor for the development of atherosclerotic CVDs. The pro-atherogenic effect of fine particulate matter is based on several basic and closely interrelated pathophysiological mechanisms: endothelial dysfunction, impaired lipid metabolism, increased oxidative stress and inflammatory reactions, impaired functioning of the vegetative nervous system and increased activity of the hemostatic system. In addition, PM 2.5 causes subclinical damage of cardiac muscle cells by several mechanisms: apoptosis, oxidative stress, decreased oxygen delivery due to coronary atherosclerosis and ischemic damage of cardiomyocytes. Highly sensitive cardiac troponins are promising markers for detecting subclinical myocardial damage in people living in polluted regions.
... Previous studies have demonstrated that PM exposure can exacerbate metabolic abnormalities in DIO and T1D models, such as potentiation to adipose inflammatory responses, cardiac fibrosis, hepatic fibrosis, and vascular endothelial dysfunction [16][17][18][40][41][42][43][44]. By contrast, less attention has been paid to the molecular mechanisms by which different metabolic diseases affect PMinduced lung toxicity. ...
... LPS-induced pulmonary inflammation enhanced the extra-pulmonary translocation of PM [62], indicating that induction of inflammatory mediators may also promote PM translocation, thereby exerting stronger systemic toxicity. Moreover, HFD resulted in more significant changes in circulatory inflammatory mediators upon PM exposure [44], while T1D enhanced systemic inflammation and oxidative stress from diesel exhaust particle exposure [40]. In the present study, DIO led to increased secretion of pro-inflammatory cytokines in the plasma, suggesting the occurrence of systemic chronic low-grade inflammation [63]. ...
Background
Pre-existing metabolic diseases may predispose individuals to particulate matter (PM)-induced adverse health effects. However, the differences in susceptibility of various metabolic diseases to PM-induced lung injury and their underlying mechanisms have yet to be fully elucidated.
Results
Type 1 diabetes (T1D) murine models were constructed by streptozotocin injection, while diet-induced obesity (DIO) models were generated by feeding 45% high-fat diet 6 weeks prior to and throughout the experiment. Mice were subjected to real-ambient PM exposure in Shijiazhuang City, China for 4 weeks at a mean PM2.5 concentration of 95.77 µg/m³. Lung and systemic injury were assessed, and the underlying mechanisms were explored through transcriptomics analysis. Compared with normal diet (ND)-fed mice, T1D mice exhibited severe hyperglycemia with a blood glucose of 350 mg/dL, while DIO mice displayed moderate obesity and marked dyslipidemia with a slightly elevated blood glucose of 180 mg/dL. T1D and DIO mice were susceptible to PM-induced lung injury, manifested by inflammatory changes such as interstitial neutrophil infiltration and alveolar septal thickening. Notably, the acute lung injury scores of T1D and DIO mice were higher by 79.57% and 48.47%, respectively, than that of ND-fed mice. Lung transcriptome analysis revealed that increased susceptibility to PM exposure was associated with perturbations in multiple pathways including glucose and lipid metabolism, inflammatory responses, oxidative stress, cellular senescence, and tissue remodeling. Functional experiments confirmed that changes in biomarkers of macrophage (F4/80), lipid peroxidation (4-HNE), cellular senescence (SA-β-gal), and airway repair (CCSP) were most pronounced in the lungs of PM-exposed T1D mice. Furthermore, pathways associated with xenobiotic metabolism showed metabolic state- and tissue-specific perturbation patterns. Upon PM exposure, activation of nuclear receptor (NR) pathways and inhibition of the glutathione (GSH)-mediated detoxification pathway were evident in the lungs of T1D mice, and a significant upregulation of NR pathways was present in the livers of T1D mice.
Conclusions
These differences might contribute to differential susceptibility to PM exposure between T1D and DIO mice. These findings provide new insights into the health risk assessment of PM exposure in populations with metabolic diseases.
... PM2.5 particles cause ultrastructural damage to mitochondria. When exposed to PM2.5, the number of mitochondria increases, which causes disruption of the mitochondrial membrane and cristae, mitochondrial vacuolization, and swelling [24][25][26][27][28]. When studying the effect of fine particles of atmospheric air on the membranes of platelet mitochondria, it was discovered that the lipid matrix of mitochondrial membranes became denser and their permeability decreased, which was characterized by the accumulation of saturated fatty acids (12:0, 14:0, 16:0, 18:0) and n -6 polyunsaturated fatty acids (20:3n-6, 20:4n-6, 22:4n-6), as well as a deficiency of n-3 polyunsaturated fatty acids. ...
... It was shown that mitochondria exposed to APM required significantly less Ca2+ to induce mitochondrial pore opening versus the control [32][33]. Also, the MMP decreased under the impact of APM, which indicated a disruption in the functioning of the mitochondrial membrane [27][28]. On the other hand, a study of the effect of APM on people living in areas with aggravated environmental stress exhibited an increase in the content of leukocytes with reduced MMP, which implied a disorder in the functioning of mitochondria [29,[34][35]. ...
The health risks associated with outdoor air pollution are of global concern. Atmospheric air pollution negatively affects a number of key aspects of human health, including the functioning of the respiratory, cardiovascular and central nervous systems, but many issues remain unresolved about the relationship between atmospheric air pollution and the development and course of pathologies. The review analyzes data from Russian and foreign sources on the effect of atmospheric particulate matter on the functional state of mitochondria. The effect of air pollution on structural changes in mitochondria, ATP synthesis, production of reactive oxygen species, damage to mitochondrial DNA, and mitochondrial membrane potential has been shown. The data presented in the review indicate the need for further studies of the functional state of mitochondria under the impact of solid particles in atmospheric air.
... The associations between PMs and CHD, stroke, arrhythmia can be explained through the following physiological mechanisms. Firstly, PMs can initiate systemic inflammation and vascular endothelial damage, which can ultimately induce atherogenesis (33). Secondly, exposure to PMs may cause systemic inflammation and oxidative stress, promoting vasoconstriction and platelet activation (34). ...
Introduction
Facing Mount Tai in the south and the Yellow River in the north, Zibo District is an important petrochemical base in China. The effect of air pollution on cardiovascular diseases (CVDs) in Zibo was unclear.
Methods
Daily outpatient visits of common CVDs including coronary heart disease (CHD), stroke, and arrhythmia were obtained from 2019 to 2022 in Zibo. Air pollutants contained fine particulate matter (PM2.5), inhalable particulate matter (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO). Distributed lag non-linear models (DLNM) including single-pollutant model in single-day (lag0-lag7) and cumulative-days (lag01-lag07), concentration-response curve, subgroup analysis, and double-pollutant model were utilized to examine the relationships of daily air pollutants on CHD, stroke, and arrhythmia. Meteorological factors were incorporated to control confounding.
Results
In single-pollutant model, NO2 was positively associated with CHD, stroke and arrhythmia, with the strongest excess risks (ERs) of 4.97% (lag07), 4.71% (lag07) and 2.16% (lag02), respectively. The highest ERs of PM2.5 on CHD, stroke and arrhythmia were 0.85% (lag01), 0.59% (lag0) and 0.84% (lag01), and for PM10, the ERs were 0.37% (lag01), 0.35% (lag0) and 0.39% (lag01). SO2 on CHD was 0.92% (lag6), O3 on stroke was 0.16% (lag6), and CO on CHD, stroke, and arrhythmia were 8.77% (lag07), 5.38% (lag01), 4.30% (lag0). No threshold was found between air pollutants and CVDs. The effects of ambient pollutants on CVDs (NO2&CVDs, PM2.5&stroke, PM10&stroke, CO&stroke, CO&arrhythmia) were greater in cold season than warm season. In double-pollutant model, NO2 was positively associated with CHD and stroke, and CO was also positively related with CHD.
Conclusion
Ambient pollutants, especially NO2 and CO were associated with CVDs in Zibo, China. And there were strong relationships between NO2, PM2.5, PM10, CO and CVDs in cold season.
... Exercise can significantly increase the metabolism of lipids and blood glucose. Clinical observations show that aerobic exercise improves blood fat levels in patients with hyperlipidemia (16) and enhance myokine and VEGF expression (17). ...
Objective: The purpose of this experimental research is to investigate the effects of High-Intensity Interval Training (HIIT) and Lipoic Acid (ALA) supplementation on VEGFR-3 of pancreatic in diabetic Wistar rats model. Materials and Methods: 20 male Wistar rats weighing 159 ± 3 gr and aged3 weeks, were randomly assigned into 4 groups:1) diabetes/sham, 2)diabetes/ ALA, 3)diabetes/exercise/sham, and 4) diabetes /exercise/ ALA. Diabetes was induced with streptozotocin (65 mg/kg dose) and Nicotinamide (120 mg/kg dose). After two weeks of familiarization with interval training, the rats started their main training, included 10 repetitions of 4 minutes of running on the treadmill with an intensity of 85-90% VO2max and 2 minutes of active rest between repetitions (5-10 m/min) for 5 sessions per week for 6 weeks. ALA supplement was taken at a dose of 20 mg/kg/day for 6 weeks. One-way ANOVA test used and Tukey's post hoc test at for analysis (P≤ 0.05). Results: HIIT has a significant effect on blood glucose (P= 0.004) and insulin (P= 0.001) and VEGFR3 (P= 0.001) of pancreatic tissue of diabetic rats. Conclusion: Lymphatic vessels play an important role in the pancreas and treat diabetes.The results of this research showed that HIIT and ALA increased lymphangiogenesis in the diabetic rat model.
... Air pollution remains a serious health question to be the familiar with environmental health and climate threat. Fine particulate matter (PM2.5) is the major risk factor for cardiovascular disease due to vascular endothelial dysfunction (Liang et al. 2021;Hayes et al. 2020). Polycyclic aromatic hydrocarbons (PAHs) are primary organic and harmful compounds bound to PM2.5 that exist ubiquitously in indoor and outdoor environments (Pietrogrande et al. 2022;Hao et al. 2018). ...
3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation.
... All indicators were monitored for at least 5 consecutive cardiac cycles, including pulse wave velocity (PWV) using Vevo®2100 Imaging System, and these indicators were averaged over consecutive cardiac cycles, as described before. 16 ...
The human cardiovascular system has evolved to accommodate the gravity of Earth. Microgravity during spaceflight has been shown to induce vascular remodeling, leading to a decline in vascular function. The underlying mechanisms are not yet fully understood. Our previous study demonstrated that miR‐214 plays a critical role in angiotensin II‐induced vascular remodeling by reducing the levels of Smad7 and increasing the phosphorylation of Smad3. However, its role in vascular remodeling evoked by microgravity is not yet known. This study aimed to determine the contribution of miR‐214 to the regulation of microgravity‐induced vascular remodeling. The results of our study revealed that miR‐214 expression was increased in the forebody arteries of both mice and monkeys after simulated microgravity treatment. In vitro, rotation‐simulated microgravity‐induced VSMC migration, hypertrophy, fibrosis, and inflammation were repressed by miR‐214 knockout (KO) in VSMCs. Additionally, miR‐214 KO increased the level of Smad7 and decreased the phosphorylation of Smad3, leading to a decrease in downstream gene expression. Furthermore, miR‐214 cKO protected against simulated microgravity induced the decline in aorta function and the increase in stiffness. Histological analysis showed that miR‐214 cKO inhibited the increases in vascular medial thickness that occurred after simulated microgravity treatment. Altogether, these results demonstrate that miR‐214 has potential as a therapeutic target for the treatment of vascular remodeling caused by simulated microgravity.
... Occupational inhalation of plastic nylon fibers has been shown to cause pulmonary inflammation known as Flock disease or Flock worker's lung [11]. Earlier studies have demonstrated that aerosolized particles like particulate matter (PM) or engineered nanomaterials (ENM) cause aberrant pulmonary function [12][13][14], pulmonary inflammation [14][15][16][17][18][19][20], systemic inflammation [17,[21][22][23][24][25], and impaired cardiovascular activity [15,17,[23][24][25][26][27][28][29][30]. ...
Background
Exposure to micro- and nanoplastic particles (MNPs) in humans is being identified in both the indoor and outdoor environment. Detection of these materials in the air has made inhalation exposure to MNPs a major cause for concern. One type of plastic polymer found in indoor and outdoor settings is polyamide, often referred to as nylon. Inhalation of combustion-derived, metallic, and carbonaceous aerosols generate pulmonary inflammation, cardiovascular dysfunction, and systemic inflammation. Additionally, due to the additives present in plastics, MNPs may act as endocrine disruptors. Currently there is limited knowledge on potential health effects caused by polyamide or general MNP inhalation.
Objective
The purpose of this study is to assess the toxicological consequences of a single inhalation exposure of female rats to polyamide MNP during estrus by means of aerosolization of MNP.
Methods
Bulk polyamide powder (i.e., nylon) served as a representative MNP. Polyamide aerosolization was characterized using particle sizers, cascade impactors, and aerosol samplers. Multiple-Path Particle Dosimetry (MPPD) modeling was used to evaluate pulmonary deposition of MNPs. Pulmonary inflammation was assessed by bronchoalveolar lavage (BAL) cell content and H&E-stained tissue sections. Mean arterial pressure (MAP), wire myography of the aorta and uterine artery, and pressure myography of the radial artery was used to assess cardiovascular function. Systemic inflammation and endocrine disruption were quantified by measurement of proinflammatory cytokines and reproductive hormones.
Results
Our aerosolization exposure platform was found to generate particles within the micro- and nano-size ranges (thereby constituting MNPs). Inhaled particles were predicted to deposit in all regions of the lung; no overt pulmonary inflammation was observed. Conversely, increased blood pressure and impaired dilation in the uterine vasculature was noted while aortic vascular reactivity was unaffected. Inhalation of MNPs resulted in systemic inflammation as measured by increased plasma levels of IL-6. Decreased levels of 17β-estradiol were also observed suggesting that MNPs have endocrine disrupting activity.
Conclusions
These data demonstrate aerosolization of MNPs in our inhalation exposure platform. Inhaled MNP aerosols were found to alter inflammatory, cardiovascular, and endocrine activity. These novel findings will contribute to a better understanding of inhaled plastic particle toxicity.
... For example, short-term and long-term exposure to ambient particles resulted in vasoconstrictor responses and endothelial function damage in animal studies (Cherng et al. 2011;Long et al. 2020;Sun et al. 2005). In vitro studies also showed that short-term PM exposure triggered endothelial activation, which was mediated by inflammation pathway and reactive oxygen species (ROS) production (Hu et al. 2016;Liang et al. 2021). Moreover, in our present review, the number of studies on PM 10 and gaseous pollutants (O 3 , NO 2 , and SO 2 ) with endothelial function is limited, and the studies had large heterogeneity of population, region and exposure characteristics, so it was still unclear whether significant associations existed among them. ...
Vascular endothelial dysfunction is an early stage to cardiovascular diseases (CVDs), but whether air pollution exposure has an effect on it remains unknown. We conducted a systematic review and meta-analysis to summarize epidemiological evidence between air pollution and endothelial dysfunction. We searched the database of PubMed, EMBASE, the Cochrane Library, and Web of Science up to November 10, 2022. Fixed and random effect models were used to pool the effect change or percent change (% change) and 95% confidence interval (95% CI) of vascular function associated with particulate matter (PM) and gaseous pollutants. I² statistics, funnel plot, and Egger’s test were used to evaluate heterogeneity and publication bias. There were 34 articles included in systematic review, and 25 studies included in meta-analysis. For each 10 µg/m³ increment in short-term PM2.5 exposure, augmentation index (AIx) and pulse wave velocity (PWV) increased by 2.73% (95% CI: 1.89%, 3.57%) and 0.56% (95% CI: 0.22%, 0.89%), and flow-mediated dilation (FMD) decreased by 0.17% (95% CI: − 0.33%, − 0.00%). For each 10 µg/m³ increment in long-term PM2.5 exposure, FMD decreased by 0.99% (95% CI: − 1.41%, − 0.57%). The associations between remaining pollutants and outcomes were not statistically significant. The effect of short-term PM2.5 exposure on FMD change was stronger in population with younger age, lower female proportion, higher mean body mass index and higher PM2.5 exposure. Cardiac or vasoactive medication might attenuate this effect. Our study provides evidence that PM2.5 exposure had adverse impact on vascular endothelial function, indicating the importance of air quality improvement for early CVD prevention.
Graphical Abstract
... tion, and tube formation, while in vivo it suppressed expression of vascular endothelial growth factor receptor 2 (VEGFR2) and platelet/endothelial cell adhesion molecule-1 (PECAM-1) and increased expression of somatostatin and its receptor in mice.66,67 PM2.5 also decreased the ECs ability to adhere to collagen type IV, tenascin, and vitronectin.67 ...
Both particulate matter and gaseous components of air pollution have already been shown to increase cardiovascular mortality in numerous studies. It is, however, important to note that on their way to the bloodstream the polluting agents pass the lung barrier. Inside the alveoli, particles of approximately 0.4–1 μm are most efficiently deposited and commonly undergo phagocytosis by lung macrophages. Not only the soluble agents, but also particles fine enough to leave the alveoli enter the bloodstream in this finite part of the endothelium, reaching thus higher concentrations in close proximity of the alveoli and endothelium. Additionally, deposits of particulate matter linger in direct proximity of the endothelial cells and may induce inflammation, immune responses, and influence endothelial barrier dysfunction thus increasing PM bioavailability in positive feedback. The presented discussion provides an overview of possible components of indoor PM and how endothelium is thus influenced, with emphasis on lung vascular endothelium and clinical perspectives.
... PM 2.5 significantly decreased the expression of vascular endothelial growth factor receptor 2 (VEGFR2) as well as elevated the expression of somatostatin (SST) and its receptor, inducing endothelial inflammation and significantly inhibiting the migration and cell viability of endothelial cells. Additionally, PM 2.5 can reduce the repair ability of vascular endothelial cells by inhibiting endothelial cell proliferation and migration [96]. Apoptosis is an important mechanism of cardiovascular toxicity induced by PM 2.5 . ...
The impacts of air pollution on public health have become a great concern worldwide. Ambient particulate matter (PM) is a major air pollution that comprises a heterogeneous mixture of different particle sizes and chemical components. The chemical composition and physicochemical properties of PM change with space and time, which may cause different impairments. However, the mechanisms of the adverse effects of PM on various systems have not been fully elucidated and systematically integrated. The Adverse Outcome Pathway (AOP) framework was used to comprehensively illustrate the molecular mechanism of adverse effects of PM and its components, so as to clarify the causal mechanistic relationships of PM-triggered toxicity on various systems. The main conclusions and new insights of the correlation between public health and PM were discussed, especially at low concentrations, which points out the direction for further research in the future. With the deepening of the study on its toxicity mechanism, it was found that PM can still induce adverse health effects with low-dose exposure. And the recommended Air Quality Guideline level of PM2.5 was adjusted to 5 μg/m³ by World Health Organization, which meant that deeper and more complex mechanisms needed to be explored. Traditionally, oxidative stress, inflammation, autophagy and apoptosis were considered the main mechanisms of harmful effects of PM. However, recent studies have identified several emerging mechanisms involved in the toxicity of PM, including pyroptosis, ferroptosis and epigenetic modifications. This review summarized the comprehensive evidence on the health effects of PM and the chemical components of it, as well as the combined toxicity of PM with other air pollutants. Based on the AOP Wiki and the mechanisms of PM-induced toxicity at different levels, we first constructed the PM-related AOP frameworks on various systems.
Graphical Abstract
... As already mentioned, a small proportion of particles directly reach the systemic circulation (Brook et al., 2010;Miller and Newby, 2020), where high levels of PM 2.5 have been correlated with an important decrease in the function of vascular endothelial cells (VECs) that cover the internal surface of blood vessels and are fundamental for the homeostasis of physiological processes (Cao, 2018). Accordingly, endothelial injury increases the release of inflammatory cytokines, leading to blood monocyte recruitment on the activated endothelial monolayer and their infiltration into the sub-endothelial space, essential in the development of atherosclerotic plaques (Lau and Baldus, 2006;Miller and Newby, 2020;Liang et al., 2021). ...
Extensive evidence indicates an association of air pollution exposure with an increased risk of cardiovascular disease (CVD) development. Fine particulate matter (PM) represents one of the main components of urban pollution, but the mechanisms by which it exerts adverse effects on cardiovascular system remain partially unknown and under investigation. The alteration of endothelial functions and inflammation are among the earliest pathophysiological impacts of environmental exposure on the cardiovascular system and represent critical mediators of PM-induced injury. In this context, endothelial stem/progenitor cells (EPCs) play an important role in vascular homeostasis, endothelial reparative capacity, and vasomotor functionality modulation. Several studies indicate the impairment of EPCs’ vascular reparative capacity due to PM exposure. Since a central source of EPCs is bone marrow (BM), their number and function could be related to the population and functional status of stem cells (SCs) of this district. In this review, we provide an overview of the potential mechanisms by which PM exposure hinders vascular repair by the alteration of progenitor and stem cells’ functionality.
Background
Previous studies on associations between short-term exposure to fine particulate matter (PM2.5) and ischemic stroke (IS) mortality reported inconclusive results. Additionally, whether and how PM2.5 and green space interact to precipitate IS deaths remains unclear. We aimed to examine the impacts of short-term exposure to PM2.5 on IS mortality and the role of green space in the association.
Methods
We collected data on daily IS deaths, daily PM2.5 concentrations, and monthly normalized difference vegetation index (NDVI) in Zibo City from 2015 to 2019. Generalised additive models were adopted to investigate the short-term impacts of PM2.5 on IS mortality, and subgroup analyses were used to examine effect modification by population characteristics. Stratified analyses by green space levels and joint effect model were conducted to test the interactions of PM2.5 and green space on IS mortality.
Results
A total of 10 799 IS deaths were included in our study. Exposure to PM2.5 was associated with an increased risk of IS mortality, with odds ratios (ORs) of 1.0263 (95% confidence interval (CI) = 1.0017, 1.0516) for each interquartile range (IQR) increase in PM2.5 on lag0 and 1.0317 (95% CI = 1.0016, 1.0627) on lag01. The links between PM2.5 and IS mortality were not significantly different across genders, ages, or PM2.5 zones. Furthermore, our results showed that the effects of PM2.5 on IS mortality were higher in low levels of green space. Specifically, for each IQR increase in PM2.5, the ORs (95% CIs) of IS death in the low level and the high level of NDVI were 1.0287 (95% CI = 1.0019, 1.0563) and 0.9934 (95% CI = 0.9296, 1.0615), respectively. In addition, PM2.5 and NDVI exhibited significant interactive effects on IS mortality, with relative excess odds due to interaction (REOI) of greater than 0.
Conclusions
Our findings showed that PM2.5 was significantly associated with increasing odds of IS mortality. Furthermore, there were synergetic impacts between PM2.5 and lack of greenness on IS mortality. Our results suggest that expanding green spaces, such as increasing park coverage and street greening, along with regulating industrial emissions to reduce PM2.5 levels, can help prevent premature deaths from IS.
Obesity, influenced by environmental pollutants, can lead to complex metabolic disruptions. This systematic review and meta-analysis examined the molecular mechanisms underlying metabolically abnormal obesity caused by exposure to a high-fat diet (HFD) and fine particulate matter (PM2.5). Following the PRISMA guidelines, articles from 2019 to 2024 were gathered from Scopus, Web of Science, and PubMed, and a random-effects meta-analysis was performed, along with subgroup analyses and pathway enrichment analyses. This study was registered in the Open Science Framework. Thirty-three articles, mainly case–control studies and murine models, were reviewed, and they revealed that combined exposure to HFD and PM2.5 resulted in the greatest weight gain (82.835 g, p = 0.048), alongside increases in high-density lipoproteins, insulin, and the superoxide dismutase. HFD enriched pathways linked to adipocytokine signaling in brown adipose tissue, while PM2.5 impacted genes associated with fat formation. Both exposures downregulated protein metabolism pathways in white adipose tissue and activated stress-response pathways in cardiac tissue. Peroxisome proliferator-activated receptor and AMP-activated protein kinase signaling pathways in the liver were enriched, influencing non-alcoholic fatty liver disease. These findings highlight that combined exposure to HFD and PM2.5 amplifies body weight gain, oxidative stress, and metabolic dysfunction, suggesting a synergistic interaction with significant implications for metabolic health.
Exposure to Particulate matter 2.5 (PM2.5) accelerates aging, causing declines in tissue and organ function, and leading to diseases such as cardiovascular, neurodegenerative, and ，musculoskeletal disorders. PM2.5 is a major environmental pollutant and an exogenous pathogen in air pollution that is now recognized as an accelerator of human aging and a predisposing factor for several age-related diseases. In this paper, we seek to elucidate the mechanisms by which PM2.5 induces cellular senescence, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, and mitochondrial dysfunction, and age-related diseases. Our goal is to increase awareness among researchers within the field of the toxicity of environmental pollutants and to advocate for personal and public health initiatives to curb their production and enhance population protection. Through these endeavors, we aim to promote longevity and health in older adults.
Despite the air quality has been generally improved in recent years, ambient fine particulate matter (PM2.5), a major contributor to air pollution, remains one of the major threats to public health. Vascular calcification is a systematic pathology associated with an increased risk of cardiovascular disease. Although the epidemiological evidence has uncovered the association between PM2.5 exposure and vascular calcification, little is known about the underlying mechanisms. The adverse outcome pathway (AOP) concept offers a comprehensive interpretation of all of the findings obtained by toxicological and epidemiological studies. In this review, reactive oxygen species generation was identified as the molecular initiating event (MIE), which targeted subsequent key events (KEs) such as oxidative stress, inflammation, endoplasmic reticulum stress, and autophagy, from the cellular to the tissue/organ level. These KEs eventually led to the adverse outcome, namely increased incidence of vascular calcification and atherosclerosis morbidity. To the best of our knowledge, this is the first AOP framework devoted to PM2.5-associated vascular calcification, which benefits future investigations by identifying current limitations and latent biomarkers.
Cooking oil fume-derived PM2.5 (COF-PM2.5) is a major source of indoor air contamination in China, which has been demonstrated to be a hazard factor of cardiovascular and cerebrovascular diseases. This study aimed to investigate the role of ROS-mediated PERK/ATF4 signaling activation in COF-PM2.5-inhibited extracorporeal tube formation in human umbilical vein endothelial cells (HUVECs). HUVECs were treated with 100 μg/mL COF-PM2.5 at different times, with or without 100 nM PERK activity inhibitor GSK2606414 (GSK) or 200 μM antioxidant N-acetylcysteine (NAC) pretreatment. Our results showed that COF-PM2.5 exposure can inhibit extracorporeal tube formation and down-regulate VEGFR2 expression in HUVECs. Furthermore, our data indicated that COF-PM2.5 exposure can activate the PERK/ATF4 signaling in HUVECs. Mechanistically, pretreatment with GSK interdicted PERK/ATF4 signaling, thereby reversing COF-PM2.5-downregulated VEGFR2 protein expression in HUVECs. Furthermore, NAC reversed VEGFR2 expression downregulated induced by COF-PM2.5 by inhibiting the upregulation of intracellular ROS levels and PERK/ATF4 signaling in HUVECs. As above, COF-PM2.5 exposure could induce ROS release from HUVECs, which in turn activate the endoplasmic reticulum PERK/ATF4 signaling and inhibit tube formation of HUVECs.
Under the background of global industrialization, PM2.5 has become the fourth-leading risk factor for ischemic stroke worldwide, according to the 2019 GBD estimates. This highlights the hazards of PM2.5 for ischemic stroke, but unfortunately, PM2.5 has not received the attention that matches its harmfulness. This article is the first to systematically describe the molecular biological mechanism of PM2.5-induced ischemic stroke, and also propose potential therapeutic and intervention strategies. We highlight the effect of PM2.5 on traditional cerebrovascular risk factors (hypertension, hyperglycemia, dyslipidemia, atrial fibrillation), which were easily overlooked in previous studies. Additionally, the effects of PM2.5 on platelet parameters, megakaryocytes activation, platelet methylation, and PM2.5-induced oxidative stress, local RAS activation, and miRNA alterations in endothelial cells have also been described. Finally, PM2.5-induced ischemic brain pathological injury and microglia-dominated neuroinflammation are discussed. Our ultimate goal is to raise the public awareness of the harm of PM2.5 to ischemic stroke, and to provide a certain level of health guidance for stroke-susceptible populations, as well as point out some interesting ideas and directions for future clinical and basic research.
Background
Short-term exposure to ambient PM2.5 and PM10 is associated with increased risk of mortality and hospital admissions for stroke. However, there is less evidence regarding the effect of exposure to PM1 on stroke incidence. We estimated the incidence risk of stroke and the attributable fractions related to short-term exposure to ambient PM1, PM2.5 and PM10 in China.
Methods
County-specific incidence of stroke was obtained from health statistics in years 2014–2019. We linked county-level mean daily concentrations of PM1, PM2.5 and PM10 with stroke incidence. We used the time stratified case-crossover design to estimate the associations between stroke incidence and exposure to PM1, PM2.5 and PM10. We also estimated the disease burden fractions attributable to PM1, PM2.5, and PM10.
Results
The study included a total of 2,193,954 stroke, from which 1,861,331 were ischemic and 332,623 were hemorrhagic stroke. PM1, PM2.5, and PM10 levels were associated with increased risks of total stroke and ischemic stroke at when assessing the associations in exposure at lag0−4 days. The increase of 10 μg/m³ in PM1, PM2.5, and PM10 was associated with total stroke, and the relative risks were 1.012 (95% confidence interval: 1.008, 1.015), 1.006 (1.004, 1.007) and 1.003 (1.002, 1.004) while the associations with ischemic stroke were 1.013 (1.010, 1.017), 1.006 (1.005, 1.008) and 1.003 (1.002, 1.004), respectively. There was no significant association between PM and risk of hemorrhagic stroke. The attributable fractions of total stroke were 6.9% (5.1%, 8.5%), 5.6% (4.2%, 6.8%) and 5.6% (3.9%, 7.1%) for PM1, PM2.5, and PM10, respectively.
Conclusions
PM1 showed a stronger association with stroke, with a larger attributable fraction of outcomes, than PM2.5 and PM10. Clean air policies should target the whole scope of PM, including PM1.
Fine particulate matter (PM2.5) exposure is a major threat to public health, and is listed as one of the leading factors associated with global premature mortality. Among the adverse health effects on multiple organs or tissues, the influence of PM2.5 exposure on cardiovascular system has drawn more and more attention. Although numerous studies have investigated the mechanisms responsible for the cardiovascular toxicity of PM2.5, the various mechanisms have not been integrated due to the variety of the study models, different levels of toxicity assessment endpoints, etc. Adverse Outcome Pathway (AOP) framework is a useful tool to achieve this goal so as to facilitate comprehensive understanding of toxicity assessment of PM2.5 on cardiovascular system. This review aims to illustrate the causal mechanistic relationships of PM2.5-triggered cardiovascular toxicity from different levels (from molecular/cellular/organ to individual/population) by using AOP framework. Based on the AOP Wiki and published literature, we propose an AOP framework focusing on the cardiovascular toxicity induced by PM2.5 exposure. The molecular initiating event (MIE) is identified as reactive oxygen species generation, followed by the key events (KEs) of oxidative damage and mitochondria dysfunction, which induces vascular endothelial dysfunction via vascular endothelial cell autophagy dysfunction, vascular fibrosis via vascular smooth muscle cell activation, cardiac dysregulation via myocardial apoptosis, and cardiac fibrosis via fibroblast proliferation and myofibroblast differentiation, respectively; all of the above cardiovascular injuries ultimately elevate cardiovascular morbidity and mortality in the general population. As far as we know, this is the first work on PM2.5-related cardiovascular AOP construction. In the future, more work needs to be done to explore new markers in the safety assessment of cardiovascular toxicity induced by PM2.5.
Cardiac fibrosis is associated with fine particulate matter (PM2.5) exposure. In addition, whether high-fat diet (HFD) could exacerbate the PM2.5-induced cardiac injury was unevaluated. Thus, this study was aimed to investigate the combined effects of PM2.5 and HFD on cardiac fibrosis. The echocardiography and histopathological analysis showed that co-exposure of PM2.5 and HFD had a significant deleterious effect on both cardiac systolic and diastolic function accompanied the myofibril disorder and myocardial fibrosis in C57BL/6 J mice than exposed to PM2.5 or HFD alone. The augmented oxidative damage and increased α-SMA area percentage were detected in heart tissue of mice exposed to PM2.5 and HFD together. PM2.5 upregulated the expressions of cardiac fibrosis-related special markers, including collagen-I, collagen-III, TGF-β1, p-Smad3 and total Smad3, which had more pronounced activations in co-exposure group. Meanwhile, the factorial analysis exhibited the synergistic interaction regarded to the combined exposure of PM2.5 and HFD. Simultaneously, PM2.5 and palmitic acid increased intracellular ROS generation and activated the TGF-β1/Smad3 signaling pathway in cardiomyocytes. While the ROS scavenger NAC had effectively attenuated the ROS level and suppressed the TGF-β1/Smad3 signaling pathway. Taken together, our results demonstrated combined exposure to PM2.5 and HFD could aggravate cardiac fibrosis via activating the ROS/TGF-β1/Smad3 signaling pathway.
Epidemiological studies have confirmed that PM2.5 could contribute to the development of atherosclerosis accompanied with lipids dysregulation. However, the lipids biomarkers involved in this progress remain largely unknown. In this study, a targeted lipidomic approach was used to find out the possible lipid biomarkers involved in the development of atherosclerosis after PM2.5 exposure or during a recovery period. Also, we assessed the pro-atherosclerosis effects of PM2.5 and follow-up influence using pulse wave (PW) Doppler ultrasound, oil red O staining and H&E staining. The vascular stiffness was elevated after 2-month PM2.5 exposure and might persist after 1-month recovery. While the lesions mostly concentrated in the aortic arch was significantly increased in 2-month PM2.5 exposure group and remained an increasing trend after 1-month recovery. The expressions of pro-inflammatory cytokines detected by Mouse Inflammation Array were elevated after ApoE-/- mice treated with PM2.5 for 2-month and restored following 1-month recovery. Yet, IL-10 was significantly decreased during 1-month recovery. Additionally, the targeted lipidomic analysis demonstrated that cholesterol ester (CE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM) were significantly increased while lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), diacylglycerol (DG), triacylglycerol (TG) were reduced after 2-month PM2.5 exposure, indicating that PM2.5 could disrupt glycerophospholipids, glycerolipids and sphingolipids metabolism. And a persistent impact of PM2.5 on glycerophospholipids and glycerolipids metabolism was found after 1-month recovery. Our study demonstrated that PM2.5-induced inflammation response might promote atherosclerotic lesions probably through lipid dysregulation, and the influence probably persisted after 1-month recovery.
The cardiovascular effects of inhaled particle matter (PM) are responsible for a substantial morbidity and mortality attributed to air pollution. Ultrafine particles, like those in diesel exhaust emissions, are a major source of nanoparticles in urban environments, and it is these particles that have the capacity to induce the most significant health effects. Research has shown that diesel exhaust exposure can have many detrimental effects on the cardiovascular system both acutely and chronically. This review provides an overview of the cardiovascular effects on PM in air pollution, with an emphasis on ultrafine particles in vehicle exhaust. We consider the biological mechanisms underlying these cardiovascular effects of PM and postulate that cardiovascular dysfunction may be implicated in the effects of PM in other organ systems. The employment of multiple strategies to tackle air pollution, and especially ultrafine particles from vehicles, is likely to be accompanied by improvements in cardiovascular health.
Aims:
Ambient air pollution is a major health risk, leading to respiratory and cardiovascular mortality. A recent Global Exposure Mortality Model, based on an unmatched number of cohort studies in many countries, provides new hazard ratio functions, calling for re-evaluation of the disease burden. Accordingly, we estimated excess cardiovascular mortality attributed to air pollution in Europe.
Methods and results:
The new hazard ratio functions have been combined with ambient air pollution exposure data to estimate the impacts in Europe and the 28 countries of the European Union (EU-28). The annual excess mortality rate from ambient air pollution in Europe is 790 000 [95% confidence interval (95% CI) 645 000-934 000], and 659 000 (95% CI 537 000-775 000) in the EU-28. Between 40% and 80% are due to cardiovascular events, which dominate health outcomes. The upper limit includes events attributed to other non-communicable diseases, which are currently not specified. These estimates exceed recent analyses, such as the Global Burden of Disease for 2015, by more than a factor of two. We estimate that air pollution reduces the mean life expectancy in Europe by about 2.2 years with an annual, attributable per capita mortality rate in Europe of 133/100 000 per year.
Conclusion:
We provide new data based on novel hazard ratio functions suggesting that the health impacts attributable to ambient air pollution in Europe are substantially higher than previously assumed, though subject to considerable uncertainty. Our results imply that replacing fossil fuels by clean, renewable energy sources could substantially reduce the loss of life expectancy from air pollution.
Epidemiological evidence suggests that fine particulate matter (PM2.5) in air pollution promotes the formation of deep venous thrombosis. However, no evidence is available on the effects of PM2.5 lead to disseminated intravascular coagulation (DIC). For the first time, this study explored the effects of PM2.5 on DIC via coagulation disorders in vivo. SD rats received intratracheal instillation of PM2.5 once every three days for one month. Doppler ultrasound showed that the pulmonary valve (PV) and aortic valve (AV) peak flow were decreased after exposure to PM2.5. Fibrin deposition and bleeding were observed in lung tissue and vascular endothelial injury was found after exposure to PM2.5. Expression of thrombomodulin (TM) in vessel was downregulated after PM2.5-treated, whereas the levels of proinflammatory factors and adhesion molecules (IL-6, IL-1β CRP, ICAM-1 and VCAM-1) were markedly elevated after exposure to PM2.5. Tissue factor (TF) and the coagulation factor of FXa were increased, while vWF was significantly lowered induced by PM2.5. Thrombin-antithrombin complex (TAT) and fibrinolytic factor (t-PA) were elevated, while there was no significantly change in the expression of anticoagulant factors (TFPI and AT-III). To clarify the relationship between PM2.5 and DIC, we examined the general diagnostic indices of DIC: PM2.5 prolonged PT and increased the expression of D-dimer but decreased platelet count and fibrinogen. In addition, the gene levels of JAK1 and STAT3 showed an upward trend, whereas there was little effect on JAK2 expression. And inflammatory factors (IL-6, IL-1β and TNF) in blood vessels of were up-reglated in PM2.5-treated rats. In summary, our results found that PM2.5 could induce inflammatory response, vascular endothelial injury and prothrombotic state, eventually resulted in DIC. It will provide new evidence for a link between PM2.5 and cardiovascular disease.
Background
Obesity leads to a chronic inflammatory state, endothelial dysfunction and hypertension.
Objective
To establish the time-course of events regarding inflammatory markers, endothelial dysfunction, systolic blood pressure (SBP) in obesity in only one experimental model.
Methods
We fed male Wistar rats (eight-week age) with a standard diet (Control - CT, n = 35), or palatable high-fat diet (HFD, n = 35) for 24 weeks. Every six weeks, 7 animals from each group were randomly selected for euthanasia. SBP and serum levels of interleukin-6, tumor necrosis factor-α, C-reactive protein, adiponectin and nitric oxide were determined. Endothelial and vascular smooth muscle functions were determined in dissected aorta and lipid peroxidation was measured. Statistical significance was set at p < 0.05.
Results
Levels of pro-inflammatory cytokines began to increase after six weeks of a high-fat diet, while those of the anti-inflammatory cytokine adiponectin decreased. Interestingly, the endothelial function and serum nitric oxide began to decrease after six weeks in HFD group. The SBP and lipid peroxidation began to increase at 12 weeks in HFD group. In addition, we showed that total visceral fat mass was negatively correlated with endothelial function and positively correlated with SBP.
Conclusion
Our results show the time-course of deleterious effects and their correlation with obesity.
Background:
Exposure to ambient fine particulate matter (PM2.5) is associated with cardiovascular mortality, but underlying pathophysiologic mechanisms are not fully understood. Hypothalamic inflammation, characterized by the activation of Inhibitor kappaB kinase 2/Nuclear factor kappaB (IKK2/NF-κB) signaling pathway, may play an important role in the pathogenesis of cardiovascular diseases. We recently demonstrated that hypothalamic inflammation is increased in mice exposed to concentrated ambient PM2.5 (CAP).
Objectives:
In the present study, we used a neuron-specific IKK2 knockout mouse model to examine the role of neural IKK2 expression and hypothalamic inflammation in the pathophysiologic effects of PM2.5.
Methods:
We assessed inflammatory and vascular responses in Nestin-creIKK2flox/flox (IKK2Neu-KO) and littermate Nestin-creIKK2flox/+ (control) mice after 4 mo of exposure to filtered air (FA) or CAP.
Results:
CAP exposure was associated with significantly higher tumor necrosis factor-α (TNFα) and interleukin (IL)-6 mRNA in the hypothalamus of control mice, but not IKK2Neu-KO mice. In addition, CAP exposure-induced increases in bronchoalveolar lavage fluid (BALF) leukocytes, pulmonary macrophage infiltration and IL-6 expression, plasma TNFα and IL-1β levels, adipose macrophage infiltration and IL-1β expression, and endothelial dysfunction were reduced or absent in IKK2Neu-KO mice compared with controls.
Conclusions:
Our findings support a role of neural IKK2 in CAP exposure-induced local and systemic pro-inflammatory cytokine expression, pulmonary and adipose inflammation, and endothelial dysfunction, thus providing insight into pathophysiologic mechanisms that may mediate effects of PM2.5 exposure. https://doi.org/10.1289/EHP2311.
Background:
Obesity contributes significantly to the development and evolution of cardiovascular disease (CVD) which is believed to be mediated by oxidative stress, inflammation and endothelial dysfunction. However, the vascular health of metabolically obese and normal weight (MONW) individuals is not completely comprehended.
Objectives:
The purpose of our study was to evaluate vascular function on the basis of a high fat diet (HFD)-MONW rabbit model.
Subjects:
Twenty four male rabbits were randomly assigned to receive either a regular diet (CD, n = 12) or a high-fat diet (18% extra fat on the regular diet, HFD, n = 12) for 6 weeks.
Results:
Body weight, TBARS and gluthathione serum levels were similar between the groups; fasting glucose, triglycerides, C reactive protein (CRP), visceral adipose tissue (VAT), triglyceride-glucose index (TyG index) were higher in the HFD group. Compared to CD, the HFD rabbits had glucose intolerance and lower HDL-cholesterol and plasma nitrites levels. Thoracic aortic rings from HFD rabbits exhibited: (a) a reduced acetylcholine-induced vasorelaxation; (b) a greater contractile response to norepinephrine and KCl; (c) an improved angiotensin II-sensibility. The HFD-effect on acetylcholine-response was reversed by the cyclooxygenase-2 (COX-2) inhibitor (NS398) and the cyclooxygenase-1 inhibitor (SC560), and the HFD-effect on angiotensin II was reversed by NS398 and the TP receptor blocker (SQ29538). Immunohistochemistry and western blot studies showed COX-2 expression only in arteries from HFD rabbits.
Conclusions:
Our study shows a positive pro-inflammatory status of HFD-induced MONW characterized by raised COX-2 expression, increase of the CRP levels, reduction of NO release and oxidative stress-controlled conditions in an early stage of metabolic alterations characteristic of metabolic syndrome. Endothelial dysfunction and increased vascular reactivity in MONW individuals may be biomarkers of early vascular injury. Therefore, the metabolic changes induced by HFD even in normal weight individuals may be associated to functional alterations of blood vessels.
Background:
Exposure to ambient air pollution increases morbidity and mortality, and is a leading contributor to global disease burden. We explored spatial and temporal trends in mortality and burden of disease attributable to ambient air pollution from 1990 to 2015 at global, regional, and country levels.
Methods:
We estimated global population-weighted mean concentrations of particle mass with aerodynamic diameter less than 2·5 μm (PM2·5) and ozone at an approximate 11 km × 11 km resolution with satellite-based estimates, chemical transport models, and ground-level measurements. Using integrated exposure-response functions for each cause of death, we estimated the relative risk of mortality from ischaemic heart disease, cerebrovascular disease, chronic obstructive pulmonary disease, lung cancer, and lower respiratory infections from epidemiological studies using non-linear exposure-response functions spanning the global range of exposure.
Findings:
Ambient PM2·5 was the fifth-ranking mortality risk factor in 2015. Exposure to PM2·5 caused 4·2 million (95% uncertainty interval [UI] 3·7 million to 4·8 million) deaths and 103·1 million (90·8 million 115·1 million) disability-adjusted life-years (DALYs) in 2015, representing 7·6% of total global deaths and 4·2% of global DALYs, 59% of these in east and south Asia. Deaths attributable to ambient PM2·5 increased from 3·5 million (95% UI 3·0 million to 4·0 million) in 1990 to 4·2 million (3·7 million to 4·8 million) in 2015. Exposure to ozone caused an additional 254 000 (95% UI 97 000-422 000) deaths and a loss of 4·1 million (1·6 million to 6·8 million) DALYs from chronic obstructive pulmonary disease in 2015.
Interpretation:
Ambient air pollution contributed substantially to the global burden of disease in 2015, which increased over the past 25 years, due to population ageing, changes in non-communicable disease rates, and increasing air pollution in low-income and middle-income countries. Modest reductions in burden will occur in the most polluted countries unless PM2·5 values are decreased substantially, but there is potential for substantial health benefits from exposure reduction.
Funding:
Bill & Melinda Gates Foundation and Health Effects Institute.
Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)–hypoxia-inducible factor-1α (HIF-1α)–vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK–HIF-1α–VEGF signaling pathway.
Electronic supplementary material
The online version of this article (doi:10.1007/s10456-016-9522-9) contains supplementary material, which is available to authorized users.
VEGF, upon binding to its endothelial cell specific receptors VEGF-R1 and VEGF-R2, can induce endothelial cell migration, proliferation and angiogenesis. However, the molecular mechanism of these effects still remains unclear. In this study, we investigated whether VEGF promotes human umbilical vascular endothelial cell (HUVEC) migration and proliferation through activator protein-1 transcription factor (AP-1) family. We first showed that VEGF induces immediate-early genes AP-1 family gene expression differentially with profound induction of JunB (both mRNA and protein) under various conditions (PBS, DMSO or control adenoviruses). The increase in AP-1 mRNA expression occurs primarily at the transcriptional level. Inhibition of AP-1 DNA binding activity by adenovirus expressing a potent dominant negative form of c-Fos (Afos) significantly attenuated VEGF-induced HUVEC migration and proliferation and cyclin D1 expression. Knockdown of JunB with adenovirus expressing JunB shRNA reduces VEGF-induced JunB expression and attenuated HUVEC migration. However the shJunB-expressing virus has no effect on VEGF-induced cyclin D1 protein expression and proliferation. These results suggest that VEGF-induced endothelial migration is mediated primarily by induction of JunB whereas promotion of endothelial proliferation by VEGF is mediated by JunB-independent AP-1 family members.
Several recent reports from large clinical trials have described the role of postprandial hyperlipidemia in the onset of atherosclerosis. In this pilot study, the effects of postprandial lipid abnormalities induced by high-fat diet loading on vascular endothelial function in type 2 diabetes were investigated and the effects of ezetimibe and statins on endothelial function were compared. In 20 patients in Study 1, peripheral arterial tonometry tests were performed before and 4h after loading to measure the reactive hyperemia index (RHI). In Study 2, the same patients were randomly allocated to ezetimibe or rosuvastatin. After 1 week of treatment, loading tests were conducted in the same manner. In Study 1, the RHI decreased from 1.86 to 1.60. There were no significant correlations between changes in RHI and the area under the curve (AUC) or coefficient of variation (CV) of each metabolic marker. In Study 2, ezetimibe treatment resulted in a significant improvement in RHI. The two drugs had comparable effects on changes in AUC. There were no significant correlations between changes in RHI and changes in AUC or changes in CV. When age, sex, drug, hemoglobin A1c, and changes in each lipid were evaluated as independent variables with RHI improvement as the dependent variable, drug differences were found to exert the greatest effect on RHI improvement using a stepwise procedure. The results of this study suggest that the progression of atherosclerosis is due to abnormalities in postprandial lipid metabolism and that ezetimibe can potentially inhibit the aggravation of vascular endothelial dysfunction after high-fat diet loading.
Vasculogenesis, the establishment of the vascular plexus and angiogenesis, branching of new vessels from the preexisting vasculature, involves coordinated endothelial differentiation, proliferation and migration. Disturbances in these coordinated processes may accompany diseases such as cancer. We hypothesized that the p53 family member p73, which regulates cell differentiation in several contexts, may be important in vascular development. We demonstrate that p73 deficiency perturbed vascular development in the mouse retina, decreasing vascular branching, density and stability. Furthermore, p73 deficiency could affect non endothelial cells (ECs) resulting in reduced in vivo proangiogenic milieu. Moreover, p73 functional inhibition, as well as p73 deficiency, hindered vessel sprouting, tubulogenesis and the assembly of vascular structures in mouse embryonic stem cell and induced pluripotent stem cell cultures. Therefore, p73 is necessary for EC biology and vasculogenesis and, in particular, that DNp73 regulates EC migration and tube formation capacity by regulation of expression of pro-angiogenic factors such as transforming growth factor-β and vascular endothelial growth factors. DNp73 expression is upregulated in the tumor environment, resulting in enhanced angiogenic potential of B16-F10 melanoma cells. Our results demonstrate, by the first time, that differential p73-isoform regulation is necessary for physiological vasculogenesis and angiogenesis and DNp73 overexpression becomes a positive advantage for tumor progression due to its pro-angiogenic capacity.Cell Death and Differentiation advance online publication, 9 January 2015; doi:10.1038/cdd.2014.214.
Production of Copper-64 (64Cu) by irradiating copper and zinc metals in a reactor was evaluated. Low specific activity 64Cu can be easily produced using thermal neutrons via 63Cu (n,γ) 64Cu reaction, while use of fast neutrons are mandatory for high specific activity 64Cu via 64Zn (n,p) 64Cu reaction. Natural copper and zinc targets were irradiated in Pakistan Research Reactor-1. Radionuclidic impurities produced
by thermal and fast neutrons were determined. Commonly available organic anion exchange resin (AG 1-X8) was used for the separation
of no-carrier-added radiocopper from neutron irradiated zinc. More than 95% 64,67Cu was recovered. The radionuclidic and chemical purity of 64Cu was determined. The specific activity of 64Cu produced by 63Cu (n,γ) and 64Zn (n,p) was compared.
KeywordsCopper and zinc metal target-Neutron irradiation-No carrier added 64,67Cu-Organic anion exchanger-Column chromatography
Purpose
Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the 68Ga-labelled bombesin analogue AMBA with metabolism-based targeting using 18F-methylcholine (18F-FCH) in nude mice bearing human prostate VCaP xenografts.
Methods
PET and biodistribution studies were performed with both 68Ga-AMBA and 18F-FCH in all VCaP tumour-bearing mice, with PC-3 tumour-bearing mice as reference. Scanning started immediately after injection. Dynamic PET scans were reconstructed and analysed quantitatively. Biodistribution of tracers and tissue uptake was expressed as percent of injected dose per gram tissue (%ID/g).
Results
All tumours were clearly visualized using 68Ga-AMBA. 18F-FCH showed significantly less contrast due to poor tumour-to-background ratios. Quantitative PET analyses showed fast tumour uptake and high retention for both tracers. VCaP tumour uptake values determined from PET at steady-state were 6.7 ± 1.4%ID/g (20–30 min after injection, N = 8) for 68Ga-AMBA and 1.6 ± 0.5%ID/g (10–20 min after injection, N = 8) for 18F-FCH, which were significantly different (p
In response to changes in wall shear stress (WSS) the vascular endothelium releases several factors, among others nitric oxide. On the basis of studies of endothelial cells in culture, suggesting that platelet endothelial cell adhesion molecule-1 (PECAM-1) is specifically involved in sensing and coupling high temporal gradients of fluid shear stress with activation of eNOS, we hypothesized that dilations of isolated skeletal muscle arterioles from PECAM-1 knockout mice (PECAM-KO) will be reduced to rapid increases in WSS elicited by increases in perfusate flow.
Small and large step increases in flow resulted in substantial dilations in arterioles of WT mice (45+/-4%), but they were markedly reduced in arterioles of PECAM-KO mice (22+/-5%). The initial slope of dilations, when WSS increased rapidly, was greater in vessels of WT than those of PECAM-KO mice (slopes: 0.378 and 0.094, respectively), whereas the second phase of dilations, when flow/shear stress was steady, was similar in the 2 groups (slopes: 0.085 and 0.094, respectively). Inhibition of eNOS significantly reduced the initial phase of dilations in arterioles from WT, but not from those of PECAM-KO mice. The calcium ionophore A23187 elicited similar NO-mediated dilation in both WT and PECAM-KO mice.
In isolated arterioles of PECAM-KO mice activation of eNOS and consequent dilation by agonists is maintained, but the dilation to high temporal gradients of wall shear stress elicited by increases in perfusate flow is reduced. Thus, we propose that PECAM-1 plays an important role in the ability of the endothelium to sense and couple high temporal gradients of wall shear stress to NO-mediated arteriolar dilation during sudden changes in blood flow in vivo.
Purpose
Lead (Pb) or cadmium (Cd) exposure has been linked to atherosclerosis. Co-exposure of these two heavy metals often occurs in humans. Recent evidence has indicated a crucial role of DNA methylation in atherosclerosis, while Pb or Cd exposure has also been shown to alter DNA methylation. However, it is still unknown whether DNA methylation plays a role in the pathological mechanism of these two heavy metals in atherosclerosis.
Approach and results
We enrolled 738 participants (12–30 years) to investigate the association among concentrations of urine Pb or Cd, the 5mdC/dG value (a global DNA methylation marker) and the carotid intima-media thickness (CIMT). When each heavy metal was modeled separately, the results showed urine Pb and Cd concentrations were positively associated with the 5mdC/dG value and CIMT, respectively. When the two heavy metals were analyzed in the same model, urinary Pb concentrations were positively associated with the 5mdC/dG value and CIMT, while urinary Cd concentrations were only positively associated with the CIMT. When Pb and Cd are simultaneously considered in the same logistic regression model, the odds ratios (OR) of thicker CIMT (greater than 75th percentile) with one unit increase in ln-Pb level was 1.67 (95% C.I. = 1.17–2.46, P = 0.005) when levels of 5mdC/dG were above 50th percentile, which is higher than 5mdC/dG bellow the 50th percentile (OR = 1.50 (95% C.I. = 0.96–2.35), P = 0.076). In structural equation model (SEM), Pb or Cd levels are directly associated with CIMT. Moreover, Pb or Cd had an indirect association with CIMT through the 5mdC/dG. When we considered Pb and Cd together, Pb levels had a direct association with CIMT and an indirect association with CIMT through the 5mdC/dG value, while Cd only had a direct association with CIMT.
Conclusions
Our findings imply that Pb and Cd exposure might be associated with subclinical atherosclerosis, and global DNA methylation might mediate Pb-associated subclinical atherosclerosis in this young population. Future effort is necessary to elucidate the causal relationship.
Objective:
Atherosclerosis is an autoimmune inflammatory disease that is closely associated with long-term exposure to fine particulate matter (PM2.5). CD4+CD25+Foxp3+ regulatory T cells (Tregs) play a critical role in the regulation of T cell-mediated immune responses, and the depletion of CD4+CD25+Foxp3+ Tregs has been thought to play a prominent role in atherosclerosis. Therefore, we investigated the association between the CD4+CD25+Foxp3+ Tregs population and atherosclerotic development in ApoE-/- mice exposed to PM2.5.
Methods:
We employed a real-world system to subject 40 ApoE-/- mice to ambient inhalation of PM2.5 (PM2.5 group, n = 20) or filtered air (FA group, n = 20) for 12 weeks. PM2.5 source apportionment, atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum level of inflammatory factors and lipid profiles, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen were quantified, respectively.
Results:
The daily average concentration of PM2.5 was 57.4 ± 25.6 μg/m3. Atherosclerotic lesions within aorta, lipid deposition and plaque accumulation in whole artery, serum levels of IL-6, TNF-α, TC and LDL-C in the PM2.5 group increased significantly compared to the FA group. Whereas, serum levels of IL-10 and TGF-β, CD4+CD25+Foxp3+ Tregs population in splenocytes, Foxp3 protein and mRNA expressions in descending aorta and spleen in the PM2.5 group decreased significantly compared to the FA group.
Conclusion:
These results suggest that PM2.5 could accelerate the development of atherosclerosis in ApoE-/- mice, which is related to CD4+CD25+Foxp3+ Tregs down-regulation, as well as lipid deposition and systemic inflammation.
Imaging arterial mechanical properties may improve vascular disease diagnosis. Pulse wave velocity (PWV) is a marker of arterial stiffness linked to cardio-vascular mortality. Pulse wave imaging (PWI) is a technique for imaging the pulse wave propagation at high spatial and temporal resolution. In this paper, we introduce adaptive PWI, a technique for the automated partition of heterogeneous arteries into individual segments characterized by most homogeneous pulse wave propagation, allowing for more robust PWV estimation. This technique was validated in a silicone phantom with a soft-stiff interface. The mean detection error of the interface was 4.67 ± 0.73 mm and 3.64 ± 0.14 mm in the stiff-to-soft and soft-to-stiff pulse wave transmission direction, respectively. This technique was tested in monitoring the progression of atherosclerosis in mouse aortas
in vivo
(
). The PWV was found to already increase at the early stage of 10 weeks of high-fat diet (3.17 ± 0.67 m/sec compared to baseline 2.55 ± 0.47 m/sec,
) and further increase after 20 weeks of high-fat diet (3.76±1.20 m/sec). The number of detected segments of the imaged aortas monotonically increased with the duration of high-fat diet indicating an increase in arterial wall property inhomogeneity. The performance of adaptive PWI was also tested in aneurysmal mouse aortas
in vivo
. Aneurysmal boundaries were detected with a mean error of 0.68±0.44 mm. Finally, initial feasibility was shown in the carotid arteries of healthy and atherosclerotic human subjects
in vivo
(
each). Consequently, adaptive PWI was successful in detecting stiffness inhomogeneity at its early onset and monitoring atherosclerosis progression
in vivo
.
Stroke is classified into two main groups depending on its aetiology; ischaemic stroke and haemorrhagic stroke which successively develop from the occlusion or rupture of an artery leading to the brain. Despite being the leading cause of human cerebral damage, there is currently no medical therapy for haemorrhagic stroke and thrombolysis with recombinant tissue plasminogen activator remains the only approved pharmacotherapy for ischaemic stroke. However, due to its short therapeutic window (first 4.5h of stroke onset) and increased risk of haemorrhage beyond this point, globally each year less than 1% of patients receive this therapy. Since, endothelial dysfunction, associated with inflammation and vascular permeability, remains the key early event in the pathogenesis of stroke, endogenous element(s) capable of countering this defect may help maintain vascular homeostasis and explain the overt differences observed in patients’ functional outcome. Accumulating evidence indicate that bone marrow-derived endothelial progenitor cells (EPCs) equipped with an inherent capacity to repair endothelial damage and differentiate into few other cell lines represent one such element. Indeed, EPCbased cell therapy, backed by rigorous preclinical, translational and early proof-of-concept, safety and feasibility clinical studies, is now considered as an important novel therapeutic approach. However, several questions relating to optimal cell dosage, delivery route and immediate and sufficient availability of cells remain to be addressed before its efficacious translation to clinical practice. In this context, ex vivo expansion of EPCs leading to an abundant generation of functional outgrowth endothelial cells offers a great opportunity to address these issues and create a novel off-the-shelf type of therapeutic product.
Clinical evidence has shown an elevated myocardial infarction (MI) risk after PM2.5 (particulate matter < 2.5 μm) exposure. Incident MI may result from rupture of vulnerable plaques. To test whether PM2.5 could promote plaque vulnerability, we exposed PM2.5 to apoe -/- mice by intranasal instillation. We detected the lipid, collagen, macrophage and smooth muscle cells (SMCs) content, and fibrous cap thickness to evaluate the plaque vulnerability. Plaques in HFD-fed mice with PM2.5 treatment for 24 weeks had increased lipid content and macrophage recruitment, and reduced collagen content, fibrous cap thickness and SMCs infiltration. Besides, 4-week exposure to PM2.5 could reduce the fibrous cap thickness, collagen content, but increase the macrophage infiltration and SMCs loss in a rapid atherosclerosis model. In existing plaques, PM2.5 could also decrease the fibrous cap thickness, collagen content. In RAW264.7, PM2.5 could promote the transformation of macrophage into foam cells. The expression of TLR4/MyD88/NFκB and CD36 were upregulated by PM2.5 treatment. Besides, the expression of CD36 promoted by PM2.5 was downregulated by the TLR4 inhibitor or MyD88/NFκB SiRNA. In conclusion, our data indicated that short- and long-term PM2.5 exposure increased plaque vulnerability. The underlying mechanism might be the PM2.5-enhanced formation of foam cells via TLR4/MyD88/NFκB pathway.
Background and aims:
The effects of a low carbohydrate/high fat (LCHF) diet on health are debated. This study aims to explore the effects of a diet with less than 20 g carbohydrates per day (LCHF) on plasma low density lipoprotein cholesterol (LDL-C) in young and healthy adults. The secondary aim is the assessment of lipid profile and peripheral blood mononuclear cells (PBMC) gene expression.
Methods:
This was a randomized controlled parallel-designed intervention study. Participants were either assigned to a three-week LCHF diet or a control group continuing habitual diet ad libitum, in both groups.
Results:
In total, 30 healthy normal weight participants completed the study. Nine subjects did not complete it due to adverse events or withdrawn consent. In the LCHF diet group (n = 15), plasma LDL-C increased from (mean ± SD) 2.2 ± 0.4 mmol/l before intervention to 3.1 ± 0.8 after, while in the control group (n = 15), LDL-C remained unchanged: 2.5 ± 0.8 mmol/l (p < 0.001 between groups). There was a significant increase in apolipoprotein B, total cholesterol, high-density lipoprotein cholesterol, free fatty acids, uric acid and urea in the LCHF group versus controls. Plasma levels of triglycerides, lipoprotein (a), glucose, C-peptide or C-reactive protein (CRP), blood pressure, body weight or body composition did not differ between the groups. PBMC gene expression of sterol regulator element binding protein 1 (SREBP-1) was increased in the LCHF group versus controls (p ≤ 0.01). The individual increase in LDL-C from baseline varied between 5 and 107% in the LCHF group.
Conclusions:
An LCHF diet for three weeks increased LDL-C with 44% versus controls. The individual response on LCHF varied profoundly.
Although the strongly causal associations were between fine particulate matter (PM2.5) and cardiovascular disease, the toxic effect and potential mechanism of PM2.5 on heart was poorly understood. Thus, the aim of this study was to evaluate the cardiac toxicity of PM2.5 exposure on human cardiomyocytes (AC16). The cell viability was decreased while the LDH release was increased in a dose-dependent way after AC16 exposed to PM2.5. The reactive oxygen species (ROS) generation and production of malondialdehyde (MDA) were increased followed by the decreasing in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). The damage of mitochondria was observed by ultra-structural analysis and MMP measurement. The apoptotic rate of AC16 were markedly elevated which was triggered by PM2.5. In addition, the proteins involved in mitochondria- mediated apoptosis pathway were measured. The protein levels of Caspase-3, Caspase-9 and Bax were up-regulated while the anti-apoptotic protein, Bcl-2 was down-regulated after AC16 exposed to PM2.5. In summary, our results demonstrated that mitochondria-mediated apoptosis pathway played a critical role in PM2.5-induced myocardial cytotoxicity in AC16, which suggested that PM2.5 may contribute to cardiac dysfunction.
Inhalation of fine particulate matter (PM2.5) is asscoiated with lung injury. High molecular weight hyaluronan (HMW-HA) is an essential constituent of extracellular matrix (ECM), exhibiting anti-oxidative and anti-inflammatory properties when administered by injection, inhalation, nebulization or gene delivery of HA synthases. The aim of the present study is to determine whether HMW-HA alleviates PM2.5-induced acute lung injury (ALI) and investigate the underlying mechanisms. We observed that HMW-HA suppressed pathological injury, inflammation, oxidative stress, edema and epithelial damage caused by PM2.5in the lungs of the rats. The protective mechanism of HMW-HA was further explored in vitro. The results elucidated that reactive oxygen species (ROS) was involved in PM2.5-induced cell apoptosis, and HMW-HA mitigated the oxidative potential of PM2.5, subsequently inhibiting phosphorylation of ASK1 at Thr845, downstream phosphorylation of p38 and JNK, and eventual apoptosis. Our study indicates that HMW-HA is a promising strategy in the prevention of PM2.5-induced pulmonary damage.
Cadmium has been proposed to be the one of the factors of atherosclerosis development, although the existing data are still controversial. The primary objective of the present study is the review and the meta-analysis of studies demonstrating the association between Cd exposure and atherosclerosis as well as review of the potential mechanisms of such association. We performed a systematic search in the PubMed-Medline database using the MeSH terms cadmium, cardiovascular disease, atherosclerosis, coronary artery disease, myocardial infarction, stroke, mortality and humans up through December 20, 2017. Elevated urinary Cd levels were associated with increased mortality for cardiovascular disease (HR = 1.34, 95% CI: 1.07-1.67) as well as elevated blood Cd levels (HR = 1.78, 95% CI: 1.24-2.56). Analysis restricted to never smokers showed similar, though more imprecise, results. Consistently, we also observed an association between Cd exposure markers (blood and urine) and coronary heart disease, stroke, and peripheral artery disease. Moreover, Cd exposure was associated with atherogenic changes in lipid profile. High Cd exposure was associated with higher TC levels (OR = 1.48, 95% CI: 1.10-2.01), higher LDL-C levels (OR = 1.31, 95% CI 0.99-1.73) and lower HDL-C levels (OR = 1.96, 95% CI: 1.09-3.55). The mechanisms of atherogenic effect of cadmium may involve oxidative stress, inflammation, endothelial dysfunction, enhanced lipid synthesis, up-regulation of adhesion molecules, prostanoid dysbalance, as well as altered glycosaminoglycan synthesis.
Aim:
Endothelial recovery, or re-endothelialization, plays an important role in intimal hyperplasia and atherosclerosis after endothelial injury. Studying the mechanisms of re-endothelialization and strategies to promote efficient endothelial recovery are still needed. Interferon-induced protein 35 (IFI35) is an IFN-γ-induced protein that plays important roles in the antivirus-related immune-inflammatory response. In this study, we tested whether overexpression IFI35 affects the proliferation and migration of endothelial cells (ECs) and re-endothelialization.
Methods:
Wire injury of the carotid artery was induced in C57BL/6 mice, which was followed by IFI35 or null adenovirus transduction. Evans blue staining and HE staining were performed to evaluate the re-endothelialization rate and neointima formation. In vitro studies, primary human umbilical vein endothelial cells (HUVECs) were transfected with Ad-IFI35 or siRNA-IFI35 to evaluate its potential roles in cell proliferation and migration. Furthermore, the potential mechanism relating inhibition of NF-κB/p65 pathway was elaborated by luciferase assay and IFI35 domain deletion assay.
Results:
In IFI35 adenovirus-transduced mice, the re-endothelialization rates at days 3, 7 were significantly reduced compared to those in null adenovirus-transduced mice (5% and 35%, vs 20% and 50%, respectively). Meanwhile, subsequent neointimal hyperplasia was obviously increased in IFI35 adenovirus-transduced mice. In vitro studies further indicated that IFI35 inhibits both EC proliferation and migration by inhibiting the NF-κB/p65 pathway. Subsequent studies demonstrated that IFI35 functionally interacted with Nmi through its NID1 domain and that knock-down of Nmi significantly mitigated the inhibitory effect of IFI35 on EC proliferation and migration.
Conclusion:
Our study revealed a novel mechanism through which IFI35 affects the proliferation and migration of ECs as well as neointima formation, specifically through inhibition of the NF-κB/p65 pathway. Thus, IFI35 is a promising target for the prevention and treatment of post-injury vascular intimal hyperplasia.
Background and aims:
Endothelial dysfunction (ED) plays a key role in the development of atherosclerotic cardiovascular disease (ASCVD). Likewise, type 2 diabetes (T2D) is a major CVD risk factor. Therefore, our objective was to explore whether long-term consumption of a Mediterranean diet (MedDiet) rich in olive oil or a low-fat diet (LF diet) was associated with an improvement in ED and whether the potential benefits were similar in patients with or without T2D in the CORDIOPREV clinical trial (NCT00924937).
Methods:
Endothelial function was measured in 805 participants who had completed follow-up ultrasound image studies, using ultrasonography of brachial artery to calculate flow mediated vasodilatation (FMD) before and after 1.5 years of intervention with a MedDiet [35% of calories from fat (22% monounsaturated) and 50% from carbohydrates] and LF diet [28% fat (12% monounsaturated) and 55% of calories from carbohydrates]. We categorized participants as patients with T2D, prediabetes, and without T2D according to the American Diabetes Association (ADA) criteria.
Results:
MedDiet increased FMD in patients with T2D [5.2 ± 0.4 at 1.5 years vs. 3.8 ± 0.4 at baseline; p=0.04] and prediabetes [4.9 ± 0.4 vs. 3.8 ± 0.4; p=0.04] and induced an improvement in FMD compared to LF diet in patients with diabetes [5.2 ± 0.4 (MedDiet) vs.3.7 ± 0.4 (LF diet); p=0.01]; whereas both diets maintained FMD stable in patients without diabetes.
Conclusions:
Habitual consumption of a MedDiet rich in extra virgin olive oil improves endothelial function in patients with prediabetes and diabetes. This takes great importance given that diet must be the cornerstone of treatment of patients with diabetes at high cardiovascular risk.
Platelets are inflammatory a nuclear cells with a well-established role in the development and manifestation of atherosclerosis. Activated platelets secrete a plethora of chemokines including CXCL4 or platelet factor 4 (PF4), CCL5, CXCL12 or stromal cell derived factor-1α (SDF-1α), CXCL16 and others, which initiate or promote local inflammatory processes at sites of vascular injury. These processes are mainly mediated by the recruitment of circulating haematopoietic stem cells, neutrophils, monocytes or lymphocytes on vascular wall. Under acute ischemic conditions platelet-derived chemokines may promote the mobilization of bone marrow-derived progenitor cells and their homing at lesion sites. This review focuses on the role of platelet-derived chemokines in inflammation and atherosclerosis. Further, we discuss the clinical value of plasma levels of chemokines in the prognosis of atherosclerotic heart disease.
Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio = 1.38, 95% confidence interval 1.12–1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated.
Rationale:
Epidemiologic evidence indicates that exposures to fine particulate matter air pollution (PM2.5) contribute to global burden of disease, primarily as a result of increased risk of cardiovascular morbidity and mortality. However, mechanisms by which PM2.5 exposure induces cardiovascular injury remain unclear. PM2.5-induced endothelial dysfunction and systemic inflammation have been implicated, but direct evidence is lacking.
Objective:
To examine whether acute exposure to PM2.5 is associated with endothelial injury and systemic inflammation.
Methods and results:
Blood was collected from healthy, non-smoking, young adults over three study periods that included episodes of elevated PM2.5 levels. Microparticles and immune cells in blood were measured by flow cytometry, and plasma cytokine/growth factors were measured using multiplexing laser beads. PM2.5 exposure was associated with elevated levels of endothelial microparticles (annexin V(+)/CD41-/CD31(+)) including subtypes expressing arterial-, venous-, and lung-specific markers, but not microparticles expressing CD62(+) These changes were accompanied by suppressed circulating levels of pro-angiogenic growth factors (EGF, sCD40L, PDGF, RANTES, GROα, and VEGF), and an increase in the levels of anti-angiogenic (TNFα, IP-10) and proinflammatory cytokines (MCP-1, MIP-1α/β, IL-6, and IL-1β), and markers of endothelial adhesion (sICAM-1 and sVCAM-1). PM2.5 exposure also was associated with an inflammatory response characterized by elevated levels of circulating CD14(+), CD16(+), CD4(+), and CD8(+), but not CD19(+) cells.
Conclusions:
Episodic PM2.5 exposures are associated with increased endothelial cell apoptosis, an anti-angiogenic plasma profile, and elevated levels of circulating monocytes, and T, but not B, lymphocytes. These changes could contribute to the pathogenic sequelae of atherogenesis and acute coronary events.
Background:
Exposure to ambient air pollution has been associated with endothelial dysfunction as reflected by short-term alterations in circulating biomarkers, but the chemical constituents and pollution sources behind the association has been unclear.
Methods:
We investigated the associations between various ambient air pollutants including gases and 31 chemical constituents and seven sources of fine particles (PM2.5) and biomarkers of endothelial function, including endothelin-1 (ET-1), E-selectin, soluble intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), based on 462 repeated measurements in a panel of 40 college students who were followed for three study periods before and after relocating from a suburban area to an urban area in Beijing, China in 2010-2011. Air pollution data were obtained from central air-monitoring stations. Linear mixed-effects models were used to estimate the changes in biomarkers associated with exposures.
Results:
Total PM2.5 mass showed few appreciable associations with examined biomarkers. However, several PM2.5 constituents and related sources showed significant associations with examined biomarkers. PM2.5 from dust/soil and several crustal and transition metals, including strontium, iron, titanium, cobalt and magnesium, were significantly associated with increases in ET-1 at 1-day average; manganese and potassium were significantly associated with increases in ICAM-1 at 2-day average; and PM2.5 from industry and metal cadmium were significantly associated with decreases in VCAM-1 at 1-day average. In addition, carbon monoxide was significantly associated with increasing ICAM-1 at 1-day and 2-day averages, whereas nitric oxide was significantly associated with decreasing ICAM-1 at 1-day and 3-day averages.
Conclusions:
Our results suggest that certain PM2.5 metal constituents were more closely associated with circulating biomarkers of endothelial function than PM2.5, and therefore highlight the research necessity to examine pollution chemical constituents in future studies.
Platelet endothelial cell adhesion molecule (PECAM-1) is highly expressed in vascular cells such as endothelial cells (ECs) and blood-borne cells like platelets and leukocytes. In ECs, this molecule controls junctional and adhesive properties. In physiological conditions, PECAM-1 supports the endothelial barrier function. In inflammation that is observed in vessels affected by atherosclerosis, the function of PECAM-1 is impaired, an event that leads to increased adhesion of neutrophils and other leukocytes to ECs, decreased vascular integrity, and higher leukocyte transmigration to the intima media. PECAM-1 has six extracellular immunoglobulin (Ig)-like domains that support attraction and adhesion of leukocytes to ECs. The cytoplasmic tail of PECAM-1 contains two tyrosine residues (Tyr-663 and Tyr-686) that could be phosphorylated by Src family protein kinases is involved in the intracellular signaling. Actually, those tyrosines are the part of the immunoreceptor tyrosine-based inhibition motifs (ITIMs) that inhibit inflammation. However, in atherosclerosis, the PECAM-1-dependent immune suppression is disturbed. This in turn facilitates recruitment of leukocytes and supports proatherogenic inflammation.
Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell dysfunction, in its broadest sense, encompasses a constellation of various nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone and redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. In this review, we trace the evolution of the concept of endothelial cell dysfunction, focusing on recent insights into the cellular and molecular mechanisms that underlie its pivotal roles in atherosclerotic lesion initiation and progression; explore its relationship to classic, as well as more recently defined, clinical risk factors for atherosclerotic cardiovascular disease; consider current approaches to the clinical assessment of endothelial cell dysfunction; and outline some promising new directions for its early detection and treatment.
Atherosclerosis is the leading cause of morbidity and mortality in the U.S., and is a multifactorial disease that preferentially occurs in regions of the arterial tree exposed to disturbed blood flow. The detailed mechanisms by which d-flow induces atherosclerosis involve changes in the expression of genes, epigenetic patterns, and metabolites of multiple vascular cells, especially endothelial cells. This review presents an overview of endothelial mechanobiology and its relation to the pathogenesis of atherosclerosis with special reference to the anatomy of the artery and the underlying fluid mechanics, followed by a discussion of a variety of experimental models to study the role of fluid mechanics and atherosclerosis. Various in vitro and in vivo models to study the role of flow in endothelial biology and pathobiology are discussed in this review. Furthermore, strategies used for the global profiling of the genome, transcriptome, miRNA-nome, DNA methylome, and metabolome, as they are important to define the biological and pathophysiological mechanisms of atherosclerosis. These "omics" approaches, especially those which derive data based on a single animal model, provide unprecedented opportunities to not only better understand the pathophysiology of atherosclerosis development in a holistic and integrative manner, but also to identify novel molecular and diagnostic targets.
Rationale:
Air pollution exposure has been shown to potentiate plaque progression in humans and animals. Our previous studies have suggested a role for oxidized lipids in mediating adverse vascular effect of air pollution. However, the types of oxidized lipids formed in response to air pollutants and how this occurs and their relevance to atherosclerosis are not fully understood.
Objective:
To investigate the mechanisms by which particulate matter <2.5 μm (PM2.5) induces progression of atherosclerosis.
Methods and results:
Atherosclerosis-prone ApoE(-/-) or LDLR(-/-) mice were exposed to filtered air or concentrated ambient PM2.5 using a versatile aerosol concentrator enrichment system for 6 months. PM2.5 increased 7-ketocholesterol (7-KCh), an oxidatively modified form of cholesterol, in plasma intermediate density lipoprotein/low-density lipoprotein fraction and in aortic plaque concomitant with progression of atherosclerosis and increased CD36 expression in plaque macrophages from PM2.5-exposed mice. Macrophages isolated from PM2.5-exposed mice displayed increased uptake of oxidized lipids without alterations in their efflux capacity. Consistent with these finding, CD36-positive macrophages displayed a heightened capacity for oxidized lipid uptake. Deficiency of CD36 on hematopoietic cells diminished the effect of air pollution on 7-KCh accumulation, foam cell formation, and atherosclerosis.
Conclusions:
Our results suggest a potential role for CD36-mediated abnormal accumulations of oxidized lipids, such as 7-KCh, in air pollution-induced atherosclerosis progression.
Key points
The development of age‐related arterial endothelial dysfunction, a key antecedent of increased cardiovascular disease (CVD) risk, is mediated largely by reduced nitric oxide bioavailability as a consequence of oxidative stress.
Mitochondria are critical signalling organelles in the vasculature, which, when dysregulated, become a source of excessive reactive oxygen species; the role of mitochondria‐derived oxidative stress in age‐related vascular dysfunction is unknown.
We show that a mitochondria‐targeted antioxidant, MitoQ, ameliorates vascular endothelial dysfunction in old mice and that these improvements are associated with the normalization of mitochondria‐derived oxidative stress and markers of arterial mitochondrial health.
These results indicate that mitochondria‐derived oxidative stress is an important mechanism underlying the development of age‐related vascular endothelial dysfunction and therefore may be a promising therapeutic target.
Mitochondria‐targeted antioxidants represent a novel strategy for preserving healthy vascular endothelial function in primary ageing and preventing age‐related CVD in humans.
Abstract
Age‐related arterial endothelial dysfunction, a key antecedent of the development of cardiovascular disease (CVD), is largely caused by a reduction in nitric oxide (NO) bioavailability as a consequence of oxidative stress. Mitochondria are a major source and target of vascular oxidative stress when dysregulated. Mitochondrial dysregulation is associated with primary ageing, but its role in age‐related endothelial dysfunction is unknown. Our aim was to determine the efficacy of a mitochondria‐targeted antioxidant, MitoQ, in ameliorating vascular endothelial dysfunction in old mice. Ex vivo carotid artery endothelium‐dependent dilation (EDD) to increasing doses of acetylcholine was impaired by ∼30% in old (∼27 months) compared with young (∼8 months) mice as a result of reduced NO bioavailability ( P < 0.05). Acute ( ex vivo ) and chronic (4 weeks in drinking water) administration of MitoQ completely restored EDD in older mice by improving NO bioavailability. There were no effects of age or MitoQ on endothelium‐independent dilation to sodium nitroprusside. The improvements in endothelial function with MitoQ supplementation were associated with the normalization of age‐related increases in total and mitochondria‐derived arterial superoxide production and oxidative stress (nitrotyrosine abundance), as well as with increases in markers of vascular mitochondrial health, including antioxidant status. MitoQ also reversed the age‐related increase in endothelial susceptibility to acute mitochondrial damage (rotenone‐induced impairment in EDD). Our results suggest that mitochondria‐derived oxidative stress is an important mechanism underlying the development of endothelial dysfunction in primary ageing. Mitochondria‐targeted antioxidants such as MitoQ represent a promising novel strategy for the preservation of vascular endothelial function with advancing age and the prevention of age‐related CVD.
Repair of the endothelium after vascular injury is crucial for preserving endothelial integrity and preventing the development of vascular disease. The underlying mechanisms of endothelial cell repair are largely unknown. We sought to investigate whether endothelial microparticles (EMP), released from apoptotic endothelial cells (ECs), influence EC repair.
Systemic treatment of mice with EMP after electrical denudation of the endothelium accelerated reendothelialization in vivo. In vitro experiments revealed that EMP uptake in ECs promotes EC migration and proliferation, both critical steps in endothelial repair. In order to dissect the underlying mechanisms, Taqman microRNA-array was performed and microRNA (miR)-126 was identified as the predominantly expressed miR in EMP. Following experiments demonstrated that miR-126 was transported into recipient HCAEC by EMP and functionally regulated the target protein sprouty-related, EVH1 domain-containing protein 1 (SPRED1). Knockdown of miR-126 in EMP abrogated EMP-mediated effects on HCAEC migration and proliferation in vitro and reendothelialization in vivo. Interestingly, after simulating diabetic conditions, EMP derived from glucose-treated ECs contained significantly lower amounts of miR-126 and showed reduced endothelial repair capacity in vitro and in vivo. Finally, expression analysis of miR-126 in circulating microparticles from 176 patients with stable coronary artery disease with and without diabetes revealed a significantly reduced miR-126 expression in circulating microparticles from diabetic patients.
Endothelial microparticles promote vascular endothelial repair by delivering functional microRNA-126 into recipient cells. In pathological hyperglycaemic conditions, EMP-mediated miR-126-induced EC repair is altered.
Based on the newly recognized role of the homeostatic chemokines in inflammation, we hypothesized that CXCL13 could modulate atherogenesis and plaque destabilization.
The study included in vivo analyses in patients with carotid atherosclerosis and in vitro experiments in cells involved in atherogenesis (ie, monocytes/macrophages, vascular smooth muscle cells [SMC], and platelets).
Our main findings were: (i) Patients with carotid atherosclerosis (n = 130) had increased plasma levels of CXCL13 with particularly high levels in symptomatic disease. (ii) CXCL13 showed increased expression within atherosclerotic carotid plaques as compared with non-atherosclerotic vessels. (iii) Within the atherosclerotic lesions, CXCR5 and CXCL13 were expressed by macrophages and SMC in all stages of plaque progression. (iv) Releasate from activated platelets and toll-like receptor activation enhanced the expression of CXCL13 in THP-1 monocytes and primary monocytes. (v) In vitro, CXCL13 exerted anti-apoptotic effects in primary monocytes, THP-1 macrophages, and vascular SMC. (vi) CXCL13 increased arginase-1, transforming growth factor-β, and interleukin-10 expression in THP-1 cells and in samples from isolated carotid plaques.
Levels of CXCL13 are increased in carotid atherosclerosis both systemically and within the atherosclerotic lesion. Based on our in vitro findings, we hypothesize a potential plaque stabilizing effects of CXCL13-CXCR5 interaction.
To evaluate the role of early-life exposure to airborne fine particulate matter (diameter, <2.5 μm [PM(2.5)]) pollution on metabolic parameters, inflammation, and adiposity; and to investigate the involvement of oxidative stress pathways in the development of metabolic abnormalities.
PM(2.5) inhalation exposure (6 h/d, 5 d/wk) was performed in C57BL/6 mice (wild type) and mice deficient in the cytosolic subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47(phox) (p47(phox-/-)) beginning at the age of 3 weeks for a duration of 10 weeks. Both groups were simultaneously fed a normal diet or a high-fat diet for 10 weeks. PM(2.5)-exposed C57BL/6 mice fed a normal diet exhibited metabolic abnormalities after exposure to PM(2.5) or FA for 10 weeks. Consistent with insulin resistance, these abnormalities included enlarged subcutaneous and visceral fat contents, increased macrophage infiltration in visceral adipose tissue, and vascular dysfunction. Ex vivo-labeled and infused monocytes demonstrated increased adherence in the microcirculation of normal diet- or high-fat diet-fed PM(2.5)-exposed mice. p47(phox-/-) mice exhibited an improvement in parameters of insulin resistance, vascular function, and visceral inflammation in response to PM(2.5).
Early-life exposure to high levels of PM(2.5) is a risk factor for subsequent development of insulin resistance, adiposity, and inflammation. Reactive oxygen species generation by NADPH oxidase appears to mediate this risk.
Platelets are a rich source of different chemokines and express chemokine receptors. CXCL4 is highly abundant in platelets and involved in promoting monocyte arrest from rolling and monocyte differentiation to macrophages. CXCL4 can also associate with CCL5 and amplify its effect on monocytes. The megakaryocyte CXCL7 gene product is proteolytically cleaved into the strong neutrophil chemoattractant, NAP-2, which has also been implicated in repair cell homing to vascular lesions. Platelet adhesion can induce release of CCL2 and CXCL8 from endothelial cells. Conversely, the chemokines CCL17, CCL22, and CXCL12 made by other cells amplify platelet activation. Platelet chemokines enhance recruitment of various hematopoietic cells to the vascular wall, fostering processes such as neointima formation, atherosclerosis, and thrombosis, but also vessel repair and regeneration after vascular injury.
The expression of PECAM, ICAM-1, VCAM-1, and E-selectin was studied in 64 samples of human coronary arteries taken from 15 explanted hearts obtained within 5 min of transplantation. Normal artery (n = 12), predominantly fibrous plaques (n = 23), and plaques containing extracellular lipid (n = 26) and three segments showing recanalization channels were studied. All endothelial cells strongly and equally expressed PECAM; positive staining was used to check that artefactual denudation of the endothelial surface had not occurred. PECAM was also present in some lipid-filled macrophages. Normal arteries showed no VCAM-1 staining but focal segments of the endothelium were positive for ICAM-1 and E-selectin. ICAM-1 was strongly and constantly expressed by the endothelium over all types of plaques and in macrophages. E-selectin expression was confined to endothelial cells and occurred on the surface in 35 per cent of fibrous and 22 per cent of lipid-containing plaques. VCAM-1 staining of surface endothelium occurred in 39 per cent of fibrous and 20 per cent of lipid-containing plaques. A population of spindle-shaped cells of macrophage type (positive for EMB11 antigen) expressed VCAM-1 in lipid-containing plaques. Adventitial vessels adjacent to plaques showed endothelial expression of ICAM-1 and E-selectin. VCAM-1 staining of adventitial vessel endothelium was associated with local lymphoid aggregation. In conclusion, the expression of cell adhesion molecules is an important element in the inflammatory component of atherosclerosis and contributes to both monocyte and lymphocyte activation and recruitment from adventitial vessels and the arterial lumen.
Abundant data link hypercholesterolaemia to atherogenesis. However, only recently have we appreciated that inflammatory mechanisms couple dyslipidaemia to atheroma formation. Leukocyte recruitment and expression of pro-inflammatory cytokines characterize early atherogenesis, and malfunction of inflammatory mediators mutes atheroma formation in mice. Moreover, inflammatory pathways promote thrombosis, a late and dreaded complication of atherosclerosis responsible for myocardial infarctions and most strokes. The new appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework for understanding the clinical benefits of lipid-lowering therapies. Identifying the triggers for inflammation and unravelling the details of inflammatory pathways may eventually furnish new therapeutic targets.
Eotaxin (CCL11) is a potent chemoattractant for eosinophils and lymphocytes. Apart from its functions in the eosinophilic system, eotaxin has been shown to be overexpressed in atherosclerosis. We therefore sought to determine whether chronic infection with Chlamydia pneumoniae or other infectious agents is correlated with concentrations of eotaxin or C-reactive protein since this mechanism could explain the finding that chronic infection stimulates smooth muscle cell migration and plaque development. Patients undergoing percutaneous coronary angioplasty (PCI) for acute coronary syndrome or stable angina were included in the study. Blood was drawn before PCI, at 6 weeks, and 6 and 12 months after coronary intervention. Eotaxin and C-reactive protein were determined by enzyme-linked immunosorbent assay (ELISA). Antibodies against Candida, C. pneumoniae, cytomegalovirus, Helicobacter pylori, and herpes simplex virus were measured by ELISA or immunofluorescence. Two hundred five consecutive patients undergoing PCI (stable angina, n = 136; acute coronary syndrome, n = 69) and 83 patients with normal coronary arteries were enrolled in the study. Eotaxin concentrations at inclusion were higher in patients with coronary artery disease than in control patients, p = .01, and comparable in patients with stable angina and those with acute coronary syndrome but did not correlate with C-reactive protein. Eotaxin concentrations at inclusion and during follow-up weakly correlated with concentrations of antibodies against C. pneumoniae, H. pylori, and herpes simplex virus but not with concentrations of antibodies against Candida or cytomegalovirus. Eotaxin concentrations and antibody titers against C. pneumoniae significantly increased following angioplasty and remained elevated thereafter. In conclusion, our data demonstrate that eotaxin concentrations are elevated independently from C-reactive protein in patients with coronary artery disease and correlate with antibodies against infectious agents known for chronic infection in humans.
Ambient particulate air pollution and daily mortality in 652 cities
- C Liu