Matrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability.
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.
Johnson
Jason Lee
JL
University of Bristol, Bristol Heart Institute, Level 7, Bristol Royal Infirmary, Marlborough Street, Bristol, BS2 8HW, UK. jason.l.johnson@bris.ac.uk
D000818:Animals; D050197:Atherosclerosis / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000187:drug effects / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D012307:Risk Factors; D012680:Sensitivity and Specificity; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology*
D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases; D053508:Matrix Metalloproteinase 12