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Smoking-related changes in LDL and atherosclerosis

Institution: University of California, San Diego
Investigator(s): Yury Miller, M.D., Ph.D.
Award Cycle: 2003 (Cycle 12) Grant #: 12KT-0104 Award: $269,500
Subject Area: Cardiovascular Disease
Award Type: New Investigator Awards

Initial Award Abstract
Tobacco smoking is a major risk factor for the development of atherosclerosis. Atherosclerosis is a disease of the vascular wall underlying heart attack and stroke, the two clinical events that cause more than 50% of deaths in the United States. Both of these events occur as a consequence of blockage in arteries of the heart or brain, respectively. Because arterial blockage is caused by build up of an atherosclerotic plaque, it is of highest importance to reveal the mechanisms of formation and growth of atherosclerotic lesions.

Atherosclerotic lesions are characterized by the presence of a large number of macrophages, the specialized cells that clean up the tissue from dying cells. These dying cells are called apoptotic cells and the process of their removal by macrophages is called phagocytosis. If dying cells are not properly removed from the tissue, they undergo necrosis and the necrotic debris causes adverse inflammatory reaction and severe complications, such as plaque rupture, thrombosis (clotting of blood) and blockage of blood flow to the heart muscle. We still do not know why and when the macrophages of atherosclerotic tissue become less efficient phagocytes, which contribute to atherosclerotic complications. On the other hand, macrophages in atherosclerotic lesions take up large quantities of lipid (fat) in the form of oxidized low-density lipoprotein (OxLDL) (cholesterol-carrying particles) and become so called foam cells, with large intracellular lipid deposits. Most importantly, OxLDL formation is promoted by tobacco smoke. The bad thing about foam cells is that they produce many active molecules, which induce further inflammation and growth of atherosclerotic lesions.

We have recently found that an early form of OxLDL, which we call minimally modified LDL (mmLDL), induces macrophage spreading due to dramatic changes in the cell cytoskeleton. Furthermore, this inhibits phagocytosis of apoptotic cells but enhances uptake of OxLDL. Both these events, if they occur in vivo, would have pro-atherogenic consequences. We have also found that these effects of mmLDL occur due to its interaction with the receptors CD14 and TLR4 on the surface of cells. The function of these two receptors on the surface of macrophages (and other cells) is to detect microbial invasion and to give the cell a signal to mobilize its anti-microbial defenses. These novel data provide an interesting link between immune responses to bacterial infection and to oxidation-specific components of self, such as mmLDL.

This proposal will test the hypothesis that interaction of mmLDL, produced by exposure to cigarette smoke, with CD14/TLR4 results in enhanced atherogenesis. The overall aim of this study is to define chemistry of mmLDL/CD14 binding as well as alterations in macrophage biology that may provide new insights into mechanisms that modulate atherosclerosis. Together with many in vitro experiments, we will also test the in vivo relevance of mmLDL/CD14/TLR4 effects on atherogenesis by using mouse models of atherosclerosis.

In summary, these studies will examine the mechanisms by which mmLDL promotes development of atherosclerosis. Because tobacco smoke is a major risk factor for atherosclerosis and, among other mechanisms, promotes atherogenic modifications of LDL and altered macrophage function, this study may help us find new ways to prevent the complications of the tobacco-related disease, atherosclerosis.

Apoptoic cell with Oxidation-Specific Epitopes are Immunogenic and proinflammaatory
Periodical: Journal of Experimental Medicine Index Medicus:
Authors: Chang, M.K., Binder, C.J., Miller, Y.I., Subbanagounder, G., Berliner, J.A., Silverman, G. ART
Yr: 2004 Vol: Nbr: Abs: Pg: 1359-1370

Toll-Like Receptor 4 Dependent and Independent Cytokine Secretion Induced by Minimally Oxidized Low-Density Lipoprotein in Macrophages
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Miller, Y.I., Viriyakosol, S., Worrall, D.S., Boullier, A., Butler, S., Witztum, J.L. ART
Yr: 2005 Vol: 25 Nbr: Abs: Pg: 1213-1219

The role of natural antibodies in atherogenesis
Periodical: Journal of Lipid Research Index Medicus:
Authors: Binder C.J., Shaw P.X., Chang M.K., Boullier A., Hartvigsen K., Horkko S., Miller Y.I., ART
Yr: 2005 Vol: 46 Nbr: Abs: Pg: 1353-1363

Toll-like receptors and atherosclerosis Oxidized LDL as an endogenous Toll -like receptor ligand
Periodical: Future Cardiol Index Medicus:
Authors: Miller Y.I. ART
Yr: 2005 Vol: 1 Nbr: Abs: Pg: 785-792

Minimally oxidized LDL offsets the apoptotic effects of extensively oxidized LDL and free cholesterol in macrophages
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Boullier A., Li, Y., Quehenberger, O., Palinski, W., Tabas, I., Witztum, J.L., and Miller ART
Yr: 2006 Vol: 26 Nbr: Abs: Pg: 1169-1176

Mutational analysis of Membrane and soluble forms of human MD-2
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Viriyakosol S, Tobias PS, Kirkland TN. ART
Yr: 2006 Vol: 281 Nbr: Abs: Pg: 11955-11964

Monoclonal Antibodies to Human Soluble MD-2
Periodical: Hybridoma Index Medicus:
Authors: Viriyakosol s, McCray PB Jr, Ashbaugh MA, Chu J, Jia HP, Weiss J and Kirkland ART
Yr: 2006 Vol: Nbr: Abs: Pg: