Abstract
Initiation of atherosclerosis is characterized by accumulation of aggregates of small lipid droplets and vesicles in the extracellular matrix of the arterial intima. The droplets and vesicles have features that suggest that they are formed from modified plasma-derived low density lipoprotein (LDL) particles. A variety of hydrolytic enzymes and prooxidative agents that could lead to extracellular assembly of LDL-derived droplets and vesicles are present in the arterial intima. In fact, in vitro studies have demonstrated that extensive oxidation of LDL and treatment of LDL with either proteolytic or lipolytic enzymes will induce LDL aggregation and fusion and treatment of LDL with cholesterol esterase will cause formation of vesicles. Fusion of LDL particles proceeds faster in vitro when they are bound to components of the extracellular matrix derived from the arterial intima, such as proteoglycans, and, depending on the type of modification, the strength of binding of modified LDL to the matrix components may either increase or decrease. In the present article, we discuss molecular mechanisms that provide clues as to how aggregated lipid droplets and vesicles may be derived from modified LDL particles. We also describe how these modified forms of LDL, by means of their trapping to the extracellular matrix, may lead to extracellular lipid accumulation in the arterial intima.—Öörni, K., M. O. Pentikäinen, M. Ala-Korpela, and P. T. Kovanen. Aggregation, fusion, and vesicle formation of modified low density lipoprotein particles: molecular mechanisms and effects on matrix interactions. J. Lipid Res. 2000. 41: 1703–1714.
Highlights
Initiation of atherosclerosis is characterized by accumulation of aggregates of small lipid droplets and vesicles in the extracellular matrix of the arterial intima
Because each type of oxidation studied is known to cause some modification of apoB-100, it is possible that such perturbations of apoB-100 structure can overcome its shielding ability, and so allow oxidized low density lipoprotein (LDL) to bind to the dimeric form of lipoprotein lipase (LPL)
The presence of aggregated lipid droplets and vesicles within the extracellular matrix (ECM) of the arterial wall can be attributed to extracellular modification of infiltrated plasma LDL particles
Summary
There are several proteolytic and lipolytic enzymes and oxidants capable of modifying LDL (Table 1). Chymase of rat mast cells can extensively hydrolyze the apoB-100 component of LDL particles [61, 62] and lysosomal proteases of macrophages degrade apoB-100 at acidic pH [63]. The arterial intima contains carboxyl ester lipase, a bile acid-dependent cholesterol esterase [72, 73] This enzyme is capable of hydrolyzing the lysophospholipids in oxidized LDL, and in the presence of cholate, the cholesteryl esters and triglycerides of LDL. Macrophages and macrophage-derived foam cells in the vessel wall synthesize lysosomal acid lipase [74]. Whether this enzyme is active in the intimal extracellular space is not known. Atherosclerotic lesions contain ceruloplasmin [80] and transition metals [80,81,82,83], both of which are potentially capable of oxidizing LDL
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