Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability.
The prevalence of atherosclerotic disease continues to increase, and despite significant reductions in major cardiovascular events with current medical interventions, an additional therapeutic window exists. Atherosclerotic plaque growth is a complex integration of cholesterol penetration, inflammatory cell infiltration, vascular smooth muscle cell (VSMC) migration, and neovascular invasion. A family of matrix-degrading proteases, the matrix metalloproteinases (MMPs), contributes to all phases of vascular remodeling. The contribution of specific MMPs to endothelial cell integrity and VSMC migration in atherosclerotic lesion initiation and progression has been confirmed by the increased expression of these proteases in plasma and plaque specimens. Endogenous blockade of MMPs by the tissue inhibitors of metalloproteinases (TIMPs) may attenuate proteolysis in some regions, but the progression of matrix degeneration suggests that MMPs predominate in atherosclerotic plaque, precipitating vulnerability. Plaque neovascularization also contributes to instability and, coupling the known role of MMPs in angiogenesis to that of atherosclerotic plaque growth, interest in targeting MMPs to facilitate plaque stabilization continues to accumulate. This article aims to review the contributions of MMPs and TIMPs to atherosclerotic plaque expansion, neovascularization, and rupture vulnerability with an interest in promoting targeted therapies to improve plaque stabilization and decrease the risk of major cardiovascular events.
Division of Vascular Surgery, Department of Surgery, Medical University of South Carolina, Charleston, S.C., USA.
Jean Marie
JM
Ruddy
John S
JS
Ikonomidis
Jeffrey A
JA
Jones
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D018450:Disease Progression; D015195:Drug Design; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic; D012422:Rupture, Spontaneous; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D061965:Matrix Metalloproteinase Inhibitors; D035683:MicroRNAs; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases