This project aims to study the effects of air particulate matter on HDL function and atherosclerosis. 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 the smaller particles are the most pathogenic. We have found that ultrafine particles (<0.18 5m) preferentially promote atherosclerosis, partly due to their high content in redox cycling chemicals and their ability to synergize with known proatherogenic mediators in the promotion of systemic tissue oxidative stress and proinflammatory effects. Indeed, we have recently reported that diesel exhaust particles, highly enriched in ultrafines, synergize with oxidized phospholipids in the induction of a large number of genes in human microvascular endothelial cells, many of which belong to antioxidant (e.g. heme oxygenase-1), proinflammatory, unfolded protein response or proapoptotic pathways of relevance in vascular inflammatory processes. These systemic effects result in the generation of dysfunctional HDL, which loses its antiinflammatory capacity or even becomes proinflammatory, despite the upregulation of antioxidant genes, an important line of defense to protect against PM toxicity. We hypothesize that exposure to ambient PM result in dysfunctional HDL and enhanced atherosclerosis via the induction of systemic prooxidant and proinflammatory effects and that a decreased antioxidant response will significantly enhance the degree of HDL dysfunction and development of atherosclerosis. We propose the following three specific aims to test our hypothesis: 1) to characterize the nature of HDL changes induced by the exposure to air particulate matter. We will use diesel exhaust as a model air pollutant to determine toxicological parameters such as effective dose and kinetics involved in the induction of HDL dysfunction. Plasma HDL will be the subject of an extensive functional and structural characterization that will include proteomic and lipidomic approaches;2) to determine the effects of decreased antioxidant response in the protection against air pollutant proinflammatory effects and atherosclerosis. We will use conditional heme oxygenase-1 KO mice in endothelial cells and macrophages to study the effect of HO-1 ablation and impaired protection against oxidative stress in a tissue-specific manner, on the degree of PM- induced HDL dysfunction and atherosclerosis;3) to evaluate the relationship between air particulate matter and human HDL dysfunction by studying whether experimental exposures to concentrated ambient particles lead to alteration in HDL antiinflammatory and antioxidant functions. This research project represents a logical extension of the candidate's previous research and thanks to the high level of institutional support given by UCLA;it will be extremely valuable to establish him as an independent investigator in the environmental field.

Public Health Relevance

This project aims to understand the effects that exposure to air particulate matter produces on HDL function and atherosclerosis, an inflammatory process within the blood vessels that is initiated and propagated by the deposition of lipids and lipoproteins and that is the cause for cardiovascular ischemic diseases such as heart attacks and strokes, responsible for the largest number of deaths in the western world. Air pollution contains both gaseous and particulate components (particulate matter) and it appears that the latter ones are mostly responsible of its cardiovascular toxicity by promoting systemic oxidative stress and proinflammatory effects that result in the loss of HDL antiinflammatory properties. This proposal is designed to characterize the functional and structural HDL modifications that air particulate matter induces with the ultimate goal of helping to develop therapeutic strategies in the future that could allow inhibiting the toxic and harmful effects of air pollutants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016959-04
Application #
8299126
Study Section
Special Emphasis Panel (ZES1-JAB-G (R3))
Program Officer
Nadadur, Srikanth
Project Start
2009-09-21
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$417,302
Indirect Cost
$116,211
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Maiseyeu, Andrei; Yang, Hui-Yu; Ramanathan, Gajalakshmi et al. (2014) No effect of acute exposure to coarse particulate matter air pollution in a rural location on high-density lipoprotein function. Inhal Toxicol 26:23-9
Miller, Mark R; McLean, Steven G; Duffin, Rodger et al. (2013) Diesel exhaust particulate increases the size and complexity of lesions in atherosclerotic mice. Part Fibre Toxicol 10:61
Li, Rongsong; Navab, Mohamad; Pakbin, Payam et al. (2013) Ambient ultrafine particles alter lipid metabolism and HDL anti-oxidant capacity in LDLR-null mice. J Lipid Res 54:1608-15
Yin, Fen; Lawal, Akeem; Ricks, Jerry et al. (2013) Diesel exhaust induces systemic lipid peroxidation and development of dysfunctional pro-oxidant and pro-inflammatory high-density lipoprotein. Arterioscler Thromb Vasc Biol 33:1153-61
Yin, Fen; Ramanathan, Gajalakshmi; Zhang, Min et al. (2013) Prooxidative effects of ambient pollutant chemicals are inhibited by HDL. J Biochem Mol Toxicol 27:172-83
Araujo, Jesus A (2011) Are ultrafine particles a risk factor for cardiovascular diseases? Rev Esp Cardiol 64:642-5
Barajas, Berenice; Che, Nam; Yin, Fen et al. (2011) NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection. Arterioscler Thromb Vasc Biol 31:58-66
Romanoski, Casey E; Che, Nam; Yin, Fen et al. (2011) Network for activation of human endothelial cells by oxidized phospholipids: a critical role of heme oxygenase 1. Circ Res 109:e27-41
Araujo, Jesus A; Barajas, Berenice; Kleinman, Michael et al. (2008) Ambient particulate pollutants in the ultrafine range promote early atherosclerosis and systemic oxidative stress. Circ Res 102:589-96