Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture.
Intimal thickening, the accumulation of cells and extracellular matrix within the inner vessel wall, is a physiological response to mechanical injury, increased wall stress, or chemical insult (e.g., atherosclerosis). If excessive, it can lead to the obstruction of blood flow and tissue ischemia. Together with expansive or constrictive remodeling, the extent of intimal expansion determines final lumen size and vessel wall thickness. Plaque rupture represents a failure of intimal remodeling, where the fibrous cap overlying an atheromatous core of lipid undergoes catastrophic mechanical breakdown. Plaque rupture promotes coronary thrombosis and myocardial infarction, the most prevalent cause of premature death in advanced societies. The matrix metalloproteinases (MMPs) can act together to degrade the major components of the vascular extracellular matrix. All cells present in the normal and diseased blood vessel wall upregulate and activate MMPs in a multistep fashion driven in part by soluble cytokines and cell-cell interactions. Activation of MMP proforms requires other MMPs or other classes of protease. MMP activation contributes to intimal growth and vessel wall remodeling in response to injury, most notably by promoting migration of vascular smooth muscle cells. A broader spectrum and/or higher level of MMP activation, especially associated with inflammation, could contribute to pathological matrix destruction and plaque rupture. Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent myocardial infarction.
Newby
Andrew C
AC
Bristol Heart Institute, University of Bristol, United Kingdom. A.Newby@bris.ac.uk
D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology*; D001808:Blood Vessels / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism*; D012421:Rupture; D017539:Tunica Intima / Q000201:enzymology / Q000473:pathology
D020782:Matrix Metalloproteinases