Pathways of catabolism of oxidized phospholipids
Initial Award Abstract
Cigarette smoking is a recognized risk factor for cardiovascular diseases although the exact mechanism by which it promotes atherosclerosis (which is cholesterol accumulation in the arteries) is not known. Cigarette smoke has been shown to contain a variety of free radicals and it has been proposed that they cause the incorporation of oxygen (oxidation of) in low-density lipoproteins (LDL). Evidence suggests that oxidized phospholipids (a major lipid of LDL) are formed in atherogenesis (formation of fatty deposits on the arterial walls) and play an important role in the oxidative modification process and that they are formed when LDL undergoes oxidation. Macrophages are cells that normally respond to inflammatory conditions and clean up damaged material. Thus, oxidized LDL (OxLDL) is taken up by macrophages “scavenger receptors” leading to cholesterol accumulation and formation of atherosclerotic plaques. Oxidized phospholipids serve as recognition markers on OxLDL leading to macrophage uptake.
Little is known about the enzymatic mechanisms involved in the degradation of these oxidized phospholipids or the way in which their degradation alters their biological effects. Various enzymes metabolize native phospholipids. Among these enzymes phospholipases are known to cleave very specific bonds within the normal phospholipid structure. Whether these phospholipases would recognize and consequently breakdown the oxidized phospholipids is an important question to be addressed. Whether or not oxidatively modified phospholipids will function as substances acted upon by these phospholipases is another important question yet to be determined. Some of the oxidized phospholipids are very reactive molecules. Whether they could alter the enzymatic activity is another question to be answered. In the case of the successful breakdown of the oxidized phospholipids by one or more phospholipase, I will examine how such modifications affect the scavenger receptor uptake of these altered molecules.
In this study I shall use pure, synthetic oxidatively modified phospholipids that are described to be part of the oxidized lipoprotein. To date, I have synthesized and characterized a large number of such molecules to mimic structures within OxLDL. I have screened these synthetic molecules against a specially made antibody that recognizes OxLDL and determined the relevant structural element of the phospholipid to which the antibody binds. I will use such synthetic oxidized phospholipids to determine whether such molecules are substrates for phospholipases. Furthermore, the products of these enzymatic activities will be tested for antibody recognition and macrophage scavenger receptor binding. The information accumulated from studying these synthetic analogs will be used to develop a model of possible, naturally occurring pathways of metabolic breakdown. Understanding the structural motifs involved in receptor recognition can lead to the development of therapeutic strategies. The potential benefit of new therapies is significant as atherosclerosis is a leading cause of death in the USA and other Western industrialized countries and about one fifth of the cases are directly caused by cigarette smoking. |
|Correlation of Antiphospholipit antibody recognition with the structure of synthetic oxidized phospholipids. Importance of schiff base formation and aldol condensation.
|Periodical: Journal of Biological Chemistry
|Authors: Friedman P, Horkko S, Steinberg D, Witzium JL, and Dennis EA