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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Special Emphasis Panel (ZES1-JAB-G (R3))
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Nadadur, Srikanth
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Kageyama, Shoichi; Hirao, Hirofumi; Nakamura, Kojiro et al. (2018) Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection: From bench-to-bedside. Am J Transplant :
Zhang, Min; Nakamura, Kojiro; Kageyama, Shoichi et al. (2018) Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury. JCI Insight 3:
Nakamura, Kojiro; Zhang, Min; Kageyama, Shoichi et al. (2017) Macrophage heme oxygenase-1-SIRT1-p53 axis regulates sterile inflammation in liver ischemia-reperfusion injury. J Hepatol 67:1232-1242
Ramanathan, Gajalakshmi; Yin, Fen; Speck, Mary et al. (2016) Effects of urban fine particulate matter and ozone on HDL functionality. Part Fibre Toxicol 13:26
Lawal, Akeem; Zhang, Min; Dittmar, Michael et al. (2015) Heme oxygenase-1 protects endothelial cells from the toxicity of air pollutant chemicals. Toxicol Appl Pharmacol 284:281-291
Li, Rongsong; Navab, Kaveh; Hough, Greg et al. (2015) Effect of exposure to atmospheric ultrafine particles on production of free fatty acids and lipid metabolites in the mouse small intestine. Environ Health Perspect 123:34-41
Ramanathan, Gajalakshmi; Araujo, Jesus A; Gornbein, Jeffrey et al. (2014) Cigarette smoking is associated with dose-dependent adverse effects on paraoxonase activity and fibrinogen in young women. Inhal Toxicol 26:861-5
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

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