Macrophage function and stability of the atherosclerotic plaque: progress report of a European project.

Abstract

Some degree of atherosclerosis is an almost invariable accompaniment of aging in developed countries, but by no means all individuals with atherosclerosis suffer its devastating thrombotic complications of myocardial infarction and stroke. Over the last few years, it has become clear that thrombotic occlusion does not generally occur in the region of full-blown fibrotic and calcified atherosclerotic plaques, but rather in the vicinity of smaller and often cell-rich regions in which a thin fibrous cap overlies a central core of extracellular lipids. These regions have been called “culprit lesions” (1, 2). Infra-red thermography has shown that such vulnerable plaques are metabolically active, and histological examinations has revealed them to be particularly rich in macrophages (3). The reasons for the rupture of culprit lesions are not entirely clear, but it is known that the prefinal event of plaque fissuring is the outcome of a complex metabolic drama in which inflammation, apoptosis and lipid metabolism are intimately intertwined (Fig 1). Excessive degradation of the various components of the extracellular matrix of the fibrous cap is considered to be an important causative factor of plaque weakening (4). It is likely that collagenases and other matrix metalloproteinases (MMPs) secreted by various cell types within the atherosclerotic plaque, especially macrophages (5, 6), play a central role in this degradation. As the oxidized low-density lipoproteins (LDL) (7) and pro-inflammatory cytokines found in atherosclerotic lesions, such as tumour necrosis factor α (TNF-α) and interleukin 1-β (IL-1β) (8), induce MMP secretion by macrophages in vitro, one possible avenue to plaque stabilisation is to inhibit MMP secretion and extracellular activation. The effects of a number of compounds on MMP activity have been tested, including naturally occurring substances Nutr Metab Cardiovasc Dis (2002) 12: 3–11