Atherosclerotic plaque rupture, with subsequent occlusive
thrombosis, is the underlying cause of most cases of
sudden cardiac death.
Matrix metalloproteinases (
MMPs) are thought to mediate the progression of stable atherosclerotic lesions to an unstable phenotype that is prone to
rupture through the destruction of strength-giving extracellular matrix (ECM)
proteins. Smooth muscle cells secrete and deposit ECM
proteins and are, therefore, considered protective against
atherosclerotic plaque destabilization. However, similar to inflammatory cells (e.g., macrophages), smooth muscle cells release numerous
MMPs that are capable of digesting ECM
proteins. Thus, the interaction of smooth muscle cells and
MMPs in
atherosclerotic plaques is complex and not fully understood. Recently, research into the roles of
MMPs and their endogenous inhibitors (tissue inhibitors of
metalloproteinases), and their effects on smooth muscle behavior during plaque destabilization has been aided by the development of reproducible animal models of plaque instability. A plethora of studies has demonstrated that
MMPs directly modulate smooth muscle behavior with both beneficial and deleterious effects on
atherosclerotic plaque stability, in addition to their canonical effects on ECM remodeling. Consequently, broad-spectrum
MMP inhibition may inhibit plaque-stabilizing mechanisms, such as smooth muscle cell growth, while conversely retarding ECM destruction and subsequent
rupture. Hence the development of selective
MMP inhibitors, that spare inhibitory effects on smooth muscle cell function, may be useful
therapies to prevent plaque
rupture and in this regard MMP-12 appears to be a particularly attractive target.