Particulate matter and atherosclerosis: role of particle size, composition and oxidative stress

Abstract

Air Pollution has been associated with significant adverse health effects leading to increased morbidity and mortality. Cumulative epidemiological and experimental data have shown that exposure to air pollutants lead to increased cardiovascular ischemic events and enhanced atherosclerosis. It appears that these associations are much stronger with the air particulate matter (PM) component and that in urban areas, the smaller particles could be more pathogenic, as a result of their greater propensity to induce systemic prooxidant and proinflammatory effects. Much is still unknown about the toxicology of ambient particulates as well as the pathogenic mechanisms responsible for the induction of adverse cardiovascular health effects. It is expected that better understanding of these effects will have large implications and may lead to the formulation and implementation of new regulatory policies. Indeed, we have found that ultrafine particles (<0.18 mum) enhance early atherosclerosis, partly due to their high content in redox cycling chemicals and their ability to synergize with known proatherogenic mediators in the promotion of tissue oxidative stress. These changes take place in parallel with increased evidence of phase 2 enzymes expression, via the electrophile-sensitive transcription factor, p45-NFE2 related transcription factor 2 (Nrf2). Exposure to ultrafine particles also results in alterations of the plasma HDL anti-inflammatory function that could be indicative of systemic proatherogenic effects. This article reviews the epidemiological, clinical and experimental animal evidence that support the association of particulate matter with atherogenesis. It also discusses the possible pathogenic mechanisms involved, the physicochemical variables that may be of importance in the greater toxicity exhibited by a small particle size, interaction with genes and other proatherogenic factors as well as important elements to consider in the design of future mechanistic studies.Extensive epidemiological evidence supports the association of air pollution with adverse health effects 123. It is increasingly being recognized that such effects lead to enhanced morbidity and mortality, mostly due to exacerbation of cardiovascular diseases and predominantly those of ischemic character 4. Indeed, in addition to the classical risk factors such as serum lipids, smoking, hypertension, aging, gender, family history, physical inactivity and diet, recent data have implicated air pollution as an important additional risk factor for atherosclerosis. This has been the subject of extensive reviews 56 and a consensus statement from the American Heart Association 7. This article reviews the supporting epidemiological and animal data, possible pathogenic mechanisms and future perspectives.

Figure 1

Idealized particle size distribution that might be observed in traffic. Particles from different sizes are generated by four modes: nucleation, aitken, accumulation and coarse mode. Also shown are the major formation and growth mechanisms of the four modes of ambient particles. V = volume, D_p = particle diameter. Source: U.S. EPA [8].

Figure 2

Possible mechanisms that link air pollution with increased cardiovascular morbidity and mortality. Air pollutants may trigger pulmonary reflexes that can activate the autonomic nervous system and result in alterations of heart rate variability and induction of dysrhythmias (in green). Air pollutants may directly affect cardiac tissue leading to the induction of dysrhythmias and/or cardiomyopathy (in yellow). Air pollutants can also enhance atherothrombotic processes that lead to the development of acute coronary syndromes (ACS) via the generation of pulmonary inflammation or direct translocation into the systemic circulation (in blue). Atherothrombotic processes include increased vascular oxidative stress, endothelial cell dysfunction, atherosclerosis and increased platelet aggregability and coagulation, among others.

Figure 3

PM effects on atherosclerotic lesions in animal studies. The relative increment in atherosclerotic lesions induced by PM exposures over filtered-air controls is displayed (%) Atherosclerotic lesions were assessed by histological analysis of aortic cross-sections, en-face assessment of the whole aorta or ultrasound biomicroscopy depending on the study. Mode of atherosclerotic lesion assessment and references for each study are shown in Table 3. HFD = High fat diet. * p < 0.05 in comparison with the corresponding filtered-air controls.

Figure 4

Stratified hierarchical response to air pollutants. Macrophages exposed to particulate matter components (e.g. DEP) respond in a dose-dependent fashion via the activation of pathways and mechanisms at various levels of action (tiers). For example, Nrf2 can induce the transcription of antioxidant genes via the antioxidant response element (ARE) in the earliest level of defense (tier 1). When the mechanisms of defense involved in one tier are not sufficient to contain the injurious stimuli, signaling pathways of the subsequent(s) tier of action may get activated, such as MAPK pathways that regulate proinflammatory genes via Activating Protein (AP) transcription factors (tier 2) or proapoptotic signals triggered by mitochondrial perturbation that can lead to activation of the mitochondrial permeability transition (PT) pore and cellular toxicity (tier 3). Modified from Li et al [123].

Figure 5

Ambient UFP triggers prooxidant effects in-vivo. Representative dorsal photograph of HO-luc transgenic mice that were exposed to concentrated UFP, concentrated PM_2.5 or filtered-air (FA) for 5 hours in a mobile exposure laboratory located in downtown Los Angeles, ~300 meters away from the I-110 freeway. Increased bioluminescence was due to a larger HO-1 upregulation response generated in tissues subject to greater oxidative stress. Mice were generated and obtained from Dr. Christopher Contag at Stanford University [62]. They contain a modified coding sequence of the luciferase gene under the control of the full HO-1 promoter. Whole-body images were acquired within 3 hours of the exposure using a cooled charged-couple device (CCD) camera at the Small Animal Imaging Center of the UCLA Crump Institute for Molecular Imaging [124] as previously described [125]. The bioluminescence signal was recorded as maximum photons/sec/cm²/steradian (p/sec/cm²/sr). Notice that the UFP-exposed mouse displays increased luciferase emissions both in the thorax and abdomen as compared with the PM_2.5 or FA-exposed mice.

Figure 6

Pathogenesis of atherosclerosis. Lipid infiltration of the artery wall originating from circulating LDL followed by oxidative modification in the subendothelial space, monocyte chemotaxis and foam cell formation are among the earliest events in atherogenesis. Monocytes differentiate into macrophages, followed by release of inflammatory mediators and a vicious cycle of inflammation. More advance stages of the disease include smooth muscle cell proliferation, formation of fibrous caps, necrotic cores, calcification, rupture, hemorrhage and thrombosis. Possible mechanisms how PM enhances atherosclerosis include: 1) Systemically translocated UFP or their chemical constituents may synergize with ox-PAPC generated within ox-LDL in the activation of proatherogenic molecular pathways in endothelial cells, 2) Inflammatory mediators released from the lungs may promote monocyte chemotaxis into the vessels, 3) PM can induce HDL dysfunction with loss of its antiinflammatory properties. Modified from Araujo and Lusis [126].

Figure 7

UFP are endocytosed by alveolar macrophages. Electron microscopy photographs of a lipid-laden alveolar macrophage harvested from an apoE^-/- mouse exposed to concentrated ambient ultrafine particles (<0.18 μm). Red arrows indicate electron-dense material corresponding to intracellular aggregates of nanoparticles. Notice the subcellular mitochondrial localization encircled by the red dotting. Source: Journal cover of Araujo et al [44].

Figure 8

Factors that may explain greater UFP's proatherogenic potential. UFP (in red) are the smallest, most numerous particles and with best pulmonary retention (top panel). UFP exhibit greater relative content of redox-active compounds (e.g. PAHs, in green) than bigger particles (mid panel). UFP's greater surface-to-mass ratio may allow reactive compounds (in green) to have increased localization towards the surface of the particle (in red) and be more bioavailable for free-radical reactions when in contact with cells (bottom panel). Estimates for the increased content of prooxidant PAHs and surface-to-mass ratio in comparison to PM_2.5are from the SCPC study [44].