Extracellular matrix metalloproteinase inducer (CD147) and membrane type 1-matrix metalloproteinase are expressed on tissue macrophages in calcific aortic stenosis and induce transmigration in an artificial valve model

ObjectiveMatrix metalloproteinases participate in remodeling of extracellular matrix, which is central to the development of aortic stenosis. Synthesis of certain matrix metalloproteinases is induced by the glycoprotein extracellular matrix metalloproteinase inducer. We investigated whether extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase are abundant in calcific aortic valve and their role in the pathogenesis of this condition.MethodsSixteen patients who underwent surgery for aortic stenosis (n = 12) or heart transplantation for ischemic cardiomyopathy (n = 4) were reviewed. Expression of extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase proteins was assessed by Western blot (n = 4 per group), immunohistochemistry for aortic stenosis (n = 12) and ischemic cardiomyopathy (n = 2), and in situ zymography (n = 3 per group). Functional relevance was investigated using an artificial valve model.ResultsExtracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase were abundant in all stenotic valves. Control valves did not stain for either protein. Double immunofluorescence colocalized extracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase to macrophages. On Western blotting, both proteins were more abundant in stenotic valves than in control valves. In situ zymography demonstrated greater gelatinolytic activity in stenotic valves than in control valves. Silencing of the extracellular matrix metalloproteinase inducer gene using small interfering RNA reduced migration of monocytes in an artificial valve model.ConclusionsExtracellular matrix metalloproteinase inducer and membrane-type 1 matrix metalloproteinase were demonstrated on macrophages in stenotic aortic valves, into which extracellular matrix metalloproteinase inducer may promote monocyte immigration. The latter protein may therefore represent a potential target to reduce the development of aortic stenosis