Most of the sudden heart attacks and strokes are caused by vulnerable fatty lesions (atherosclerotic plaques) in vessel walls that are undetectable by clinical evaluation. In conditions such as diabetes and aging, LDL, the lipoprotein that carries """"""""bad"""""""" cholesterol, becomes modified by oxidation and other chemical reactions. The body may recognize the oxidized LDL (oxLDL) as """"""""foreign"""""""" and produce autoantibodies against it. These antibodies can bind to oxLDL and form immune complexes (oxLDL-IC), which are cleared by scavenging cells, the macrophages. Macrophages then transform into lipid-loaded cells (foam cells) and start secreting inflammatory products (cytokines). Cytokines released by macrophages and other activated cells act to promote plaque rupture and harmful consequences such as blood clotting. This proposal focuses on foam cell activation and survival induced by oxLDL-IC. The receptor Fc gamma Rl mediates the uptake of oxLDL-IC but the possible role of scavenger receptors in the uptake of oxLDL-IC and whether or not cross linking of two receptors trigger distinct signaling pathways required to elicit an enhanced macrophage response have not been examined. Our data demonstrate that exposure of U937 cells to oxLDL-IC led to increased cell survival, and to translocation and secretion of sphingosine kinase (SK). SK and its product sphingosine-1-phosphate (S1P) are known to be involved in cell proliferation and suppression of apoptosis (cell death). The central hypothesis of this application is that the process by which exposure of macrophages to oxLDL-IC leads to activation and transformation into foam cells involves the engagement of Fc gamma Rl and scavenger receptors, triggering sphingolipid signaling mechanisms that suppress apoptosis and result in extended release of cytokines. The following specific aims will be addressed: 1) characterize the involvement of specific macrophage receptors in the process of macrophage response to oxLDL-IC, and determine if sphingolipid components of oxLDL-IC contribute to the signaling that results in release of cytokines;and 2) characterize the activated downstream sphingolipid signaling response to oxLDL, and evaluate the effect of oxLDL-IC on SK1 activity and S1P signaling. These studies should uncover mechanisms by which oxLDL-IC suppress apoptosis of foam cells, and reveal specific targets in the signaling pathway that can have therapeutic implications for blocking cytokine release and to prevent formation of vulnerable plaques.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079274-05
Application #
7788856
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2006-04-01
Project End
2012-06-30
Budget Start
2010-04-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$283,532
Indirect Cost
Name
Medical University of South Carolina
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Al Gadban, Mohammed M; Alwan, Mohamed M; Smith, Kent J et al. (2015) Accelerated vascular disease in systemic lupus erythematosus: role of macrophage. Clin Immunol 157:133-44
Klein, Richard L; Hammad, Samar M; Baker, Nathaniel L et al. (2014) Decreased plasma levels of select very long chain ceramide species are associated with the development of nephropathy in type 1 diabetes. Metabolism 63:1287-95
Al Gadban, Mohammed M; German, Jashalynn; Truman, Jean-Philip et al. (2012) Lack of nitric oxide synthases increases lipoprotein immune complex deposition in the aorta and elevates plasma sphingolipid levels in lupus. Cell Immunol 276:42-51
Hammad, Samar M; Truman, Jean-Philip; Al Gadban, Mohammed M et al. (2012) ALTERED BLOOD SPHINGOLIPIDOMICS AND ELEVATED PLASMA INFLAMMATORY CYTOKINES IN COMBAT VETERANS WITH POST-TRAUMATIC STRESS DISORDER. Neurobiol Lipids 10:2
Truman, Jean-Philip; Al Gadban, Mohammed M; Smith, Kent J et al. (2012) Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low-density lipoprotein (LDL) and oxidized LDL immune complexes: role in phagocytosis and cytokine release. Immunology 136:30-45
Hammad, Samar M (2011) Blood sphingolipids in homeostasis and pathobiology. Adv Exp Med Biol 721:57-66
Truman, Jean-Philip; Al Gadban, Mohammed M; Smith, Kent J et al. (2011) Acid sphingomyelinase in macrophage biology. Cell Mol Life Sci 68:3293-305
Smith, Kent J; Twal, Waleed O; Soodavar, Farzan et al. (2010) Heat shock protein 70B' (HSP70B') expression and release in response to human oxidized low density lipoprotein immune complexes in macrophages. J Biol Chem 285:15985-93
Lee, Mi-Hye; Hammad, Samar M; Semler, Andrea J et al. (2010) HDL3, but not HDL2, stimulates plasminogen activator inhibitor-1 release from adipocytes: the role of sphingosine-1-phosphate. J Lipid Res 51:2619-28
Al Gadban, Mohammed M; Smith, Kent J; Soodavar, Farzan et al. (2010) Differential trafficking of oxidized LDL and oxidized LDL immune complexes in macrophages: impact on oxidative stress. PLoS One 5:

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