Worldwide,
cardiovascular disease (CVD) is the leading cause of death. Most CVD-related deaths are caused by years of preceding
atherogenesis and the extensive development of
atherosclerotic plaques, some of which may
rupture to cause
myocardial infarction. Macrophages are known to have a role in almost all stages of
atherosclerosis, by both initiating
atherosclerotic plaques and degrading them through the secretion of
proteolytic enzymes leading to
rupture. This review summarizes the literature on the role of macrophages and their proteolytic activity on
proteins in the extracellular matrix (ECM) of the
atherosclerotic plaque with a view to suggest a novel approach for identification of vulnerable plaques and turnover by the use of a new type of
biomarker. The PubMed database was searched using the terms macrophages, foam cells,
atherosclerosis, CVD, ECM remodeling,
biomarker, neoepitope,
matrix metalloproteinase (
MMP), and
protease.
Atherosclerotic plaques are primarily composed of the
protein type I and III
collagen, and smaller quantities of
elastin and
proteoglycans. Macrophages secrete an array of
proteases, including
MMPs,
cathepsins, and aggrecanases, with the ability to degrade most of the constituents of the ECM of the
atherosclerotic plaque. At present it is not clear which
proteases play pivotal roles at distinct stages of pathogenesis, rather that the combined proteolytic potential with some
proteases at early stages and other at later stages may result in plaque
rupture. This macrophage-mediated proteolysis and remodeling of the ECM play important roles in many stages of
atherosclerosis. The degradation fragments of these ECM events are specific neoepitopes, which are released into the circulation. The identification of these pathologically relevant neoepitopes leads to novel
biomarkers able to identify the formation and degradation of plaques providing different biological information than traditionally used
biomarkers.