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Oxidized lipids and programmed cell death in atherosclerosis

Institution: University of California, San Diego
Investigator(s): Mi-Kyung Chang, M.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8FT-0101 Award: $69,116
Subject Area: Cardiovascular Disease
Award Type: Postdoctoral Fellowship Awards
Abstracts

Initial Award Abstract
A heart attack or myocardial infarction is America's number one killer. It usually happens because of a blockage in a coronary artery, which prevents blood from being delivered to heart tissue. Usually arterial blockage is caused by atherosclerosis, a form of artery disease that is characterized by a buildup of fatty deposits and chronic inflammation along inner artery walls. These deposits gradually develop into plaques that narrow blood vessels and eventually lead to rupture of the plaque, clotting of the blood (thrombosis) and interruption of blood flow, which lead to clinical event (myocardial infarction or stroke). Cigarette smoking and high blood cholesterol levels are major risk factors for the development of atherosclerosis. However, the mechanisms involved in the development of atherosclerosis are complex and remain unknown. Usually, someone who has a high blood cholesterol level has a high level of low-density lipoprotein (LDL) in blood. LDL is composed of lipid (fat, mainly cholesterol) and protein, and is considered the “bad”" form of cholesterol because it tends to collect in artery walls and develop into atherosclerotic plaque. When LDL is oxidized in the arterial wall, it becomes “oxidized LDL". Oxidized LDL is preferentially accumulated by macrophages, the scavenger cells found in early atherosclerotic lesions, and contributes to the cholesterol accumulation that is typical of atherosclerosis. Oxidized LDL and its related compounds also have properties that induce inflammation in the arterial walls which further develop the atherosclerotic plaque.

Apoptosis is an active form of cell death in which cells neatly commit “programmed suicide” to be taken up and cleared by neighboring cells in normal tissues. Apoptosis plays an important role in maintaining proper turnover of cells in the body by removing damaged or aged cells. Normally the clearance of apoptotic cells occurs swiftly and efficiently so that it is hard to detect apoptotic cells in normal tissues. If apoptotic cells are not cleared up promptly noxious contents of the cell will leak out and induce direct tissue injury and inflammation. In atherosclerotic lesions, a lot of apoptotic cells are present in addition to the fatty deposits. These apoptotic cells may be one of the causative factors that disrupts the atherosclerotic plaque, which in turn causes the acute blood clotting and vessel blockage leading to myocardial infarction.

In preliminary studies I found that apoptotic cells present oxidatively modified lipid and/or lipid-protein molecules on their surfaces, and that these oxidized molecules could serve as “markers” for the clearance of apoptotic cells. I hypothesize that apoptotic cells may play a similar role to oxidized LDL in the development of advanced atherosclerotic lesion. The proposed studies will seek to define the mechanism involved in the clearance of apoptotic cells and the impact of their defective clearance on atherosclerosis. These findings will increase our knowledge of the etiology of atherosclerosis, which in turn could lead to prevention and improved therapies.

Final Report
Atherosclerosis is the form of artery disease that is characterized by a buildup of fatty deposits and chronic inflammation along inner artery walls. These deposits gradually develop into atherosclerotic plaques that narrow blood vessels and eventually interrupt blood flow, which lead to clinical events, such as myocardial infarction and stroke. Cigarette smoking is one of major risk factors for premature atherosclerosis. Among the several proatherogenic effects of smoking, oxidizing effect by free radicals on lipid peroxidation could be a major factor for atherogenesis.

Low density lipoprotein (LDL) is composed of lipid (fat) and protein, and is considered “bad” cholesterol because it tends to collect in artery walls and develop into atherosclerotic plaque. When LDL is oxidized in the arterial wall, it becomes “Oxidized LDL”. Oxidized LDL (OxLDL) and its many oxidatively modified lipids or lipid-protein compounds have been demonstrated to play an important role in atherosclerosis by not only directly inducing inflammation in the artery wall and develop atherosclerotic plaque but also by inducing profound immune response. In addition to lipid deposits, a lot of dying cells are found in atherosclerotic lesion. Although the causative role of dying cells in atherosclerosis is unknown, accumulation of dying cells in lesions may be a factor involved in the formation of the chronic inflammatory lesion and autoimmune response that could modulate the formation of atherosclerotic lesion.

In preliminary studies I found that the dying cell present “oxidatively modified lipid and/or lipid-protein compound” on its surface, and that those compounds could play an important role as marker for clearance of apoptotic cells. Based on these finding we hypothesized that “oxidatively modified lipid and/or lipid-protein compound” of dying cells in the atherosclerotic lesion might share identity to oxidized LDL and could be an equivalently potential factor as oxidized LDL in the development of advanced atherosclerotic lesion.

The overall aim of this proposal was to define the “oxidatively modified lipid and/or lipid-protein compounds” that are generated during cell death and the impact of those oxidized compound of dying cells on the inflammatory and autoimmune responses that occur in atherosclerosis. I have demonstrated that dying cells generate oxidized phospholipids, which are also found on oxidized LDL and are known to exert proinflammatory responses, such as recruitment of inflammatory cells into the atherosclerotic lesion. Furthermore I have demonstrated that dying cells that containing those oxidized phospholipids can induce inflammatory response, which in turn can contribute to atherosclerosis. Also I found that overloading of dying cells could induce remarkable immune response against “oxidatively modified lipid and/or lipid-protein compound”. This finding imply that dying cells are capable of initiating immune response and that “oxidatively modified lipid and/or lipid-protein compound” are in part responsible for this.

These results suggest the oxidative moieties of dying cells in atheroslcertoic lesions could trigger inflammation and immune responses and like oxidized LDL, may contribute to the progression of this chronic inflammatory disease. Further studies will be needed to exploit the mechanisms responsible for inflammatory and immune response induced by dying cells.

The proposed study will increase our knowledge of mechanisms involved in development of atherosclerosis in relation to defective clearance of apoptotic cells and the mechanisms by which dying cells can induce inflammatory and autoimmune responses. In turn, such information could lead to prevention and improved therapies to atherosclerosis.
Publications

Oxidation-specific monoclonal antibodies bind to apoptotic cells and inhiit their phagocytosis by macrophages
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Chang M-K, Bergmark C, Lauria A, Horrko S, Han KH, Witztum J ART
Yr: 1999 Vol: 96 Nbr: Abs: Pg: 6353-6358

A human monoclonal Fab cloned from phage display library binds to OxLDL and apoptotic cells and inhibits their uptake by macrophage
Periodical: Circulation Index Medicus:
Authors: Shaw PX, Horrko S, Chang M-K, et al ART
Yr: 1999 Vol: 100 Nbr: 18 Abs: Pg: 539-540

Natural antibodies with the T15 idiotype may act atherosclerosis, apoptosis clearance, and protective immunity
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Shaw PX, Horrko S, Chang M-K, et al ART
Yr: 200 Vol: 105 Nbr: 12 Abs: Pg: 1731-1740

Immunological responses to oxidized LDL
Periodical: Free Radical Biology and Medicine Index Medicus:
Authors: Horrko S, Binder CJ, Shaw PX, et al ART
Yr: 2000 Vol: 28 Nbr: 12 Abs: Pg: 1771-1779

Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor gamma
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Han KH, Chang M-K, Boullier A, et al ART
Yr: 2000 Vol: 105 Nbr: 12 Abs: Pg: 1731-1740

12/15-Lipoxygenase colocalizes with F-Actin and enhances actin polymerization in macrophages phagocytosing apoptotic cells
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Miller YI, Chang M-K, Funk CD, Feramisco JR, Witztum J ART
Yr: 2001 Vol: 276 Nbr: 22 Abs: Pg: 19431-19439

Human-derived anti-oxidized ldl autoantibody blocks uptake of oxidized ldl by macrophages and localizes to atheroslcerotic lesions in vivo
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Shaw PX, Horrko S, Chang M-K, et al ART
Yr: 2001 Vol: 21 Nbr: 8 Abs: Pg: 1333-1339