Phospholipase A2 modification of lipoproteins: potential effects on atherogenesis.

Abstract

Cardiovascular diseases are the leading causes of mortality and morbidity among elderly in westernized societies (1). The main causes for the clinical complications associated with cardiovascular diseases are atherosclerotic plaque formation and thrombosis (2). The pathogenesis of atherosclerosis is complex and multi factorial but one of the most important risk factors linked to coronary artery disease is increased levels of the plasma ApoB-100 containing lipoproteins low density lipoproteins (LDL) and very low density lipoproteins (VLDL). The atherosclerotic lesion is characterized by a focal accumulation of ApoB-100 lipoproteins, extracellular matrix, and cells in the arterial intima, accompanied by an inflammatory reaction (3,4). In vivo and in vitro data support the hypothesis that sulfated extracellular proteoglycans (PG) may be responsible for the selective retention of LDL in the arterial wall (5,6). These interactions facilitate further modifications of LDL such as oxidation, proteolysis, and lipolysis, which alter physicochemical properties of the lipoproteins and may contribute to atherogenesis (3). Studies from our laboratory and from others have consistently demonstrated the presence of abundant group IIA secretory non-pancreatic phospholipase A2 (snpPLA2) in human atherosclerotic lesions (7-10). In addition, snpPLA2 can also be detected in the circulation, and hyperphospholipasemia is usually closely associated to pathological conditions that include a systemic inflammatory response (11). Recently, it was demonstrated that circulating levels of snpPLA2 were associated with an increased risk for coronary artery disease in humans and predicted disease progression in this group of patients (12). The physiological function(s) of snpPLA2 is still not clear, but it has been suggested to play an important role as a mediator of inflammation (13). The lipolytic action of snpPLA2 generates non-esterified fatty acids (NEFA) and lyso-phospholipids from phosphoglyceride-aggregates. Lipoproteins appear to be physiological substrates for snpPLA2 in vivo (14). An LDL particle consists of a neutral lipid core made mainly of triglycerides and cholesteryl esters surrounded by amphipatic phospholipids and unesterified cholesterol with an embedded ApoB-100 molecule. SnpPLA2 may be proatherogenic by two mechanisms (15). First, by generating NEFA and lyso-phospholipids at sites of lipoprotein retention in the arterial wall. These products may directly affect the functionality of the surrounding cells and serve as precursors for the production of proinflammatory factors such as eicosanoids, platelet-activating factor, and lysophosphatidic acid. If locally released in the arterial intima these reactive components may induce and sustain an inflammatory response. Second, modification of lipoproteins by snpPLA2 in the circulation or focally in the arterial wall may lead to alterations of the lipoprotein properties and generation of lipoprotein particles with increased atherogenicity.